Pediatric PET Imaging 0387288368, 9780387288369

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Pediatric PET Imaging

Pediatric PET Imaging Martin Charron, MD, FRCP(C) Professor, Department of Radiology, University of Toronto, Division Head of Nuclear Medicine, Head of Research for Diagnostic Imaging, Senior Associate Scientist, Research Institute, The Hospital for Sick Children, Toronto, Canada

Editor

Martin Charron, MD, FRCP(C) Professor, Department of Radiology University of Toronto Division Head of Nuclear Medicine Head of Research for Diagnostic Imaging Senior Associate Scientist Research Institute The Hospital for Sick Children Toronto M5G 1X8 Canada

Library of Congress Control Number: 2005932082 ISBN-10: 0-387-28836-8 ISBN-13: 978-0387-28836-9 Printed on acid-free paper. © 2006 Springer Science+Business Media, Inc. All rights reserved. This work may not be translated or copied in whole or in part without the written permission of the publisher (Springer Science+Business Media, Inc., 233 Spring Street, New York, NY 10013, USA), except for brief excerpts in connection with reviews or scholarly analysis. Use in connection with any form of information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed is forbidden. The use in this publication of trade names, trademarks, service marks, and similar terms, even if they are not identified as such, is not to be taken as an expression of opinion as to whether or not they are subject to proprietary rights. While the advice and information in this book are believed to be true and accurate at the date of going to press, neither the authors nor the editors nor the publisher can accept any legal responsibility for any errors or omissions that may be made. The publisher makes no warranty, express or implied, with respect to the material contained herein. Printed in the United States of America. 9

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To my wife Teran, without whose love and support this book would not be possible and who is the better part of me, To my children Sophie, Claire, George, Annie, and Mimi for providing meaning to my life, To the memory of my dad who taught me what is important, To my mother who made me what I am and gave me the necessary patience to deal with the aforementioned kids!

Foreword I

Positron emission tomography (PET) has been at the forefront of functional and molecular imaging for a number of years. The future of diagnostic imaging depends upon the ability to change from imaging anatomy to examining the processes at work in the body. The fact that there are now monographs examining particular aspects of PET, such as this book on the examination of children, speaks to the newly won maturity of PET. The authors are to be congratulated for the timely appearance of this volume. In recent years, PET has transformed the contributions of nuclear medicine to the diagnosis, staging, and follow-up of patients with cancer. Children with cancer deserve the very best and most compassionate care that society can provide. Ultimately the greatest compassion we can offer as physicians is to provide the best possible care. Those charged with creating public policy in the context of diagnostic medicine must make common cause with physicians and other scientists to ensure that that best possible care is realized at the bedside. All of the evidence suggests that PET is central to such optimal cancer care. In addition to the distinguished cast of physicians and researchers who contributed to this book, I welcome the contributions from technologists who are a key part of the interaction between the diagnostic process and the sick or potentially sick child. Good care is contingent upon putting parents and child at ease, and the technologist has a lead role in this. Scientists, working alongside physicians and physician-scientists, have done much to ensure that PET continues to evolve in at least two directions. One direction is the technical development of imaging devices, particularly in the form of hybrid detector systems to image both biochemistry and morphology simultaneously; combined positron emission and x-ray computed tomography (PET-CT) is an example of this. In another direction, new radio-labeled molecular probes are emerging that will take PET beyond the mapping of regional glucose metabolism. PET will continue to evolve in ways we can now see but dimly. The inherent power of PET is represented for me by the fact that it has been the first technology in diagnostic imaging to serve vii

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not only in the diagnosis of individual patients but also to address the wider issue of our understanding of disease mechanisms and the localization of biochemical events in the living body. Pediatric PET Imaging clearly represents the importance of PET. The reader will be enriched with useful clinical information for daily practice and alerted to recent developments so as to be in a position to anticipate and benefit from evolution in a field that is in a constant process of change. It has been said that developments in molecular biology and genomics will cause medicine to change more in the next few decades than it has over the past several centuries. I have no doubt that PET will have an important role to play at the “bedside” in realizing the benefits of our growing understanding of the molecular basis of disease and its treatment. I am sure my colleagues will join me in welcoming Pediatric PET Imaging as a timely synthesis of our current knowledge in pediatric PET, coming as it does at the cusp of so much progress in diagnostic methods and in our ability to image disease. Brian Lentle, MD Emeritus Professor of Radiology University of British Columbia

Foreword II

While the importance of PET in the understanding of physiologic and pathological conditions in adults has been well described, this is the first book to be published concerning the importance of PET imaging in pediatric patients. The use of PET in medicine is a relatively recent development. In 1968 Kuhl and Edwards at the University of Pennsylvania introduced the concept of emission tomography and built a device to measure the regional distribution of single gamma emitters. In 1975 Ter-Pogossian and colleagues at Washington University described the first instrument designed to image positron emitting radioligands. Interest in using short-lived positron emitters for the study of biologic functions in humans was greatly enhanced by the development of the 14Cdeoxyglucose method for measuring region cerebral glucose metabolism (rCMRgl) autoradiographically in animals by Sokoloff and colleagues at the National Institute of Mental Health and Reivich at the University of Pennsylvania in 1977. It was clear that adapting this method to studies in humans offered great potential, and in late 1973 Reivich, Kuhl, and Alavi discussed the possibility of labeling deoxyglucose with a gamma-emitting radionuclide for measuring rCMRgl in humans. We contacted Alfred Wolf at Brookhaven National Laboratory, and at a joint meeting in December 1973 Wolf suggested using 18F to label the glucose analogue fluorodeoxyglucose (FDG) because of its relatively long half-life and its low positron energy. By 1975, 18F-FDG was successfully synthesized by Ido in Wolf’s laboratory in sufficient quantity to be shipped to the University of Pennsylvania for human studies. In preparation for these studies, the Mark IV scanner at the University of Pennsylvania was equipped with high-energy collimators to image the 511Kev gamma rays emitted by 18F-FDG. In August of 1976, the first study of rCMRgl in humans was performed at the University of Pennsylvania. The development of the 18F-FDG method for the measurement of regional cerebral glucose metabolism in humans, together with the method for the measurement of regional cerebral blood flow using 15O labeled water pioneered by Herscovitch, Raichle and coinvestigators in 1983 gave birth to functional imaging of the human ix

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brain. Since then, hundreds of tracers labeled with positron-emitting radionuclides have been developed to measure various physiologic and biochemical processes in the human body. In recognition of the stimulus provided to this field, FDG was nominated as the “molecule of the century” by Henry Wagner in 1996 at the meeting of the Society of Nuclear Medicine. FDG continues to be the most widely used PET tracer. Pediatric PET Imaging amply documents the great importance that these developments have had in the field of pediatrics. The application of PET methodology to pediatric patients has expanded our understanding of disorders ranging from attention deficit hyperactivity disorder, learning disorders, and neuropsychiatric disorders to epilepsy, central nervous system tumors, cardiac disorders, and infectious processes, among others. This book is extremely informative for health care professionals caring for children with these conditions including nuclear medicine technologists performing the PET scan, researchers preparing a proposal utilizing PET in the pediatric population, nuclear medicine physicians interpreting the PET scan, and clinicians treating the patients. Martin Reivich, MD Emeritus Professor University of Pennsylvania

Preface

Positron emission tomography (PET), a powerful research tool 20 years ago, has recently gained widespread application in oncology and is now a procedure clinically available on each continent. Despite the fact only a few PET centers are dedicated to children, data from Children’s Oncology Group indicate that virtually all children in North America have easy access to a PET center. As the table of contents of this book indicates, clinical and research applications of PET for children with cancer represent only a fraction of the current pediatric uses for PET technology. Small animal PET scanners are now available commercially as there has been tremendous interest in applying PET technology to in vivo imaging of animal models. PET can dynamically image trace amounts of radiopharmaceuticals in vivo. By applying appropriate tracer kinetic models, tracer concentrations can be determined quantitatively. In addition to superior spatial resolution and quantitative potential, PET also offers much greater sensitivity (i.e., number of y-rays detected per unit injected dose) than single photon emission computed tomography (SPECT). Furthermore, the biologic ubiquity of the elements that are positron emitters gives PET unprecedented power to image the distribution and kinetics of natural and analog biologic tracers. Because of the exquisite sensitivity of detection systems to y-ray emission, these biologic probes can be introduced in trace amounts (nano- or even picomolar concentrations) that do not disturb the biologic process under investigation. By combining a tracer that is selective for a specific biochemical pathway, an accurate tracer kinetic model, and a dynamic sequence of quantitative images from the PET scanner, it is possible to estimate the absolute rates of biologic processes in that pathway. Examples of such processes that have been successfully measured with PET include regional cerebral and myocardial blood flow, rates of glucose utilization, rates of protein synthesis, cerebral and myocardial oxygen consumption, synthesis of neurotransmitters, enzyme assays, and receptor assays. In summary, some of the distinctive advantages of PET are its exquisite sensitivity, the flexible chemistry, and the better imaging characteristics of PET isotopes. Thus PET provides access to xi

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biological processes that is well beyond the scope of current MR technology. Although FDG has been successfully and widely employed in oncology, it has not demonstrated significant uptake in some tumors in adults. Some other positron emitter tracers seem to be more promising. Among the many radiopharmaceuticals that show great potential is the serotonin precursor 5-hydroxytryptophan (5-HTP) labeled with 11C, which shows increased uptake in carcinoids. Another radiopharmaceutical in development for PET is 11C L-DOPA, which seems to be useful in visualizing endocrine pancreatic tumors such as Hyperinsulinism (Chapter 26). PET is now widely used in children in most health care institutions in North America, Europe, and Asia. When an imaging modality is used routinely in children, it usually implies that it has reached a certain maturity, that the modality in question has achieved widespread recognition in the clinical field by peers. Yet there are no PET books available to pediatricians that offer a comprehensive review of diseases and/or issues specific to children. Often those diseases are not reviewed in sufficient details in “adult textbooks,” and issues specific to children not discussed at all (e.g., sedation, dosage). The goal of this text is to fill those gaps. We did a comprehensive review of all clinical and research applications of PET in children and gathered a distinguished cast of authorities from the Americas, Europe, and Australia to summarize their experience with PET and to perform exhaustive reviews of the literature in their areas of interest. Although this book focuses on practical applications, it includes detailed reviews of current and future research applications. Pediatric PET Imaging offers a comprehensive review of practical issues specific to the pediatric population such as sedation, radiopharmaceutical dosage, approach to imaging children, and “tips” for technologists. For those interested in the research applications of PET, the book also offers practical reviews of regulations, IRB requirements, ethical issues, and biological effects of low level radiation exposure. The scope of the pathologies reviewed in this work is much wider than what is seen in the typical “adult textbook.” The physiopathology and the imaging findings of the most common cancers afflicting children are scrutinized. Many chapters of this book review nononcological applications such as neurological and psychiatric diseases, some unique to children, some affecting both children and adults. Some chapters are thorough reviews of inflammation, or variants of it (FUO, IBD, and infection). New applications that appear to have the potential to offer great clinical usefulness, such as imaging of hyperinsulinism, are included. Because the biodistribution of FDG and the “normal variants” are different in children, two imaging atlases are included to allow readers to become familiar with those idiosyncrasies. The book also reviews principles of operations and instrumentation challenges specific to children. A chapter is dedicated to coincidence imaging, as some of us do not have access to dedicated PET imaging. (One could also foresee similar imaging findings with coincidence imaging and Tc99 –glucose scanning, which may become a viable alter-

Preface

native to PET imaging in some precise clinical applications.) Finally, there are also expert reviews of multimodality imaging such as PET/CT and PET/MR. Pediatric PET Imaging addresses typical concerns about imaging children and will be useful to the nuclear medicine physician who sees an occasional pediatric patient in his/her clinical practice. This book may also become a bedside reference for nuclear physicians and radiologists who practice only pediatric imaging. The book is also designed to be useful to all pediatricians, especially oncologists and radiation therapists, clinicians, or researchers looking to learn how the many recent imaging innovations in PET can influence their own areas of interests. Finally, this book offers a comprehensive review of research issues valuable to scientists. PET will offer many new solutions to current and future problems of medicine. As a scientific community, we need to ensure that the current or proposed uses of PET are evaluated with the greatest accuracy, rigor, and appropriateness within the inherent limits of our current economic infrastructure. One of our many ethical challenges is to choose which pathology should first be scrutinized. As PET technology continues to mature, we are seeing the beginning of a powerful merger among biology, pharmacology, and imaging, and with it the true birth of in vivo biologic imaging. Because of the flexible chemistry inherent to positron emitting isotopes, PET is vested with tremendous potential to evaluate the physiopathology of pediatric diseases. Martin Charron, MD, FRCP(C) Toronto, Canada

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Contents

Foreword I by Brian Lentle . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Foreword II by Martin Reivich . . . . . . . . . . . . . . . . . . . . . . . . . . Preface . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Contributors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Section 1 1

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Basic Science and Practical Issues

The Nuclear Imaging Technologist and the Pediatric Patient . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Maria Green

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Sedation of the Pediatric Patient . . . . . . . . . . . . . . . . . . . . Robin Kaye

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The Biologic Effects of Low-Level Radiation . . . . . . . . . . Martin Charron

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Dosage of Radiopharmaceuticals and Internal Dosimetry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Xiaowei Zhu

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Pediatric PET Research Regulations . . . . . . . . . . . . . . . . . Geoffrey Levine

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Issues in the Institutional Review Board Review of PET Scan Protocols . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Robert M. Nelson

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Ethics of PET Research in Children . . . . . . . . . . . . . . . . . Suzanne Munson, Neir Eshel, and Monique Ernst

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Physics and Instrumentation in PET . . . . . . . . . . . . . . . . Roberto Accorsi, Suleman Surti, and Joel S. Karp

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How to Image a Child by PET–Computed Tomography . . . . . . . . . . . . . . . . . . . . . . Sue C. Kaste and M. Beth McCarville

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Coincidence Imaging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Girish Bal, Stefaan Vandenberghe, and Martin Charron

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Section 2 Oncology 11

Brain Tumors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Michael J. Fisher and Peter C. Phillips

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Lymphoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Christopher J. Palestro, Josephine N. Rini, and Maria B. Tomas

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Neuroblastoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Barry L. Shulkin

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Wilms’ Tumor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Sue C. Kaste and Jeffrey S. Dome

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Primary Bone Tumors . . . . . . . . . . . . . . . . . . . . . . . . . . . . Robert Howman-Giles, Rodney J. Hicks, Geoffrey McCowage, and David K. Chung

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Soft Tissue Sarcomas . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Marc P. Hickeson

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Other Tumors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Jian Qin Yu and Martin Charron

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Section 3

Neurology and Psychiatry

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The Developing Brain . . . . . . . . . . . . . . . . . . . . . . . . . . . . Lorcan A. O’Tuama and Paul R. Jolles

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Neurodevelopmental and Neuropsychiatric Disorders . . . . . . . . . . . . . . . . . . . . . . . Marianne Glanzman and Josephine Elia

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Epilepsy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Nicolaas I. Bohnen and James M. Mountz

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Neurotransmitter Imaging . . . . . . . . . . . . . . . . . . . . . . . . Alan J. Fischman and Rajendra D. Badgaiyan

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Section 4 Other Applications 22

Cardiovascular Applications . . . . . . . . . . . . . . . . . . . . . . . Miguel Hernandez-Pampaloni

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Fever of Unknown Origin . . . . . . . . . . . . . . . . . . . . . . . . . Hongming Zhuang and Ghassan El-Haddad

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Infection and Inflammation . . . . . . . . . . . . . . . . . . . . . . . Marc P. Hickeson

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Inflammatory Bowel Disease . . . . . . . . . . . . . . . . . . . . . . Jean-Louis Alberini and Martin Charron

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26A Hyperinsulinism of Infancy: Noninvasive Differential Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . Maria-João Santiago-Ribeiro, Nathalie Boddaert, Pascale De Lonlay, Claire Nihoul-Fekete, Francis Jaubert, and Francis Brunelle 26B

Hyperinsulinism of Infancy: Localization of Focal Forms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Olga T. Hardy and Charles A. Stanley

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Multimodal Imaging Using PET and MRI . . . . . . . . . . . . Thomas Pfluger and Klaus Hahn

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Current Research Efforts . . . . . . . . . . . . . . . . . . . . . . . . . . Fabio Ponzo and Martin Charron

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Section 5

Imaging Atlas

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PET–Computed Tomography Atlas . . . . . . . . . . . . . . . . . M. Beth McCarville

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Common Artifacts on PET Imaging . . . . . . . . . . . . . . . . . Peeyush Bhargava and Martin Charron

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Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Contributors

Roberto Accorsi, PhD Research Scientist, Nuclear Medicine, Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA Jean-Louis Alberini, MD Nuclear Medicine Department, Cancer Research Center R. Huguenin, 92210 Saint-Cloud, France Rajendra D. Badgaiyan, PhD, MD Assistant Professor, Department of Radiology, Harvard University, Department of Radiology, Massachusetts General Hospital, Boston, MA 02114, USA Girish Bal, PhD Post-Doctorial Fellow, Nuclear Medicine, Department of Radiology, Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA Peeyush Bhargava, MD Assistant Professor, Department of Radiology, Columbia University College of Physicians and Surgeons, Attending in Nuclear Medicine, St. Luke’s Roosevelt Hospital Center, New York, NY 10019, USA Nathalie Boddaert, MD, PhD Service de Radiologie Pédiatrique, Hôpital Necker-Enfants Malades, 75015 Paris, France Nicolaas I. Bohnen, MD, PhD Associate Professor, Departments of Radiology and Neurology, Division of Nuclear Medicine, University of Michigan, Ann Arbor, MI 48109, USA xix

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Francis Brunelle, MD Professor and Chairman, Department of Radiology, Service de Radiologie Pédiatrique, Hôpital Necker-Enfants Malades, 75015 Paris, France Martin Charron, MD, FRCP(C) Professor, Department of Radiology, University of Toronto, Division Head of Nuclear Medicine, Head of Research for Diagnostic Imaging, Senior Associate Scientist, Research Institute, The Hospital for Sick Children, Toronto M5G 1X8, Canada David K. Chung, BSc (Med), MB BS, FRACP, DDU, DCH Physician, Department of Nuclear Medicine, The Children’s Hospital at Westmead, Sydney, Australia Pascale De Lonlay, MD, PhD Département de Métabolisme et Pédiatrie, Hôpital Necker-Enfants Malades, 75015 Paris, France Jeffrey S. Dome, MD Associate Member, Department of Hematology-Oncology, St. Jude Faculty, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA Ghassan El-Haddad, MD Chief Fellow, Nuclear Medicine Training Program, Hospital of the University of Pennsylvania, Philadelphia, PA 19104, USA Josephine Elia, MD Assistant Professor, Department of Psychiatry, University of Pennsylvania, Medical Co-Director of the ADHD Center, Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA Monique Ernst, MD, PhD Staff Clinician, National Institute of Mental Health, Section of Developmental and Affective Neuroscience, Bethesda, MD 20892, USA Neir Eshel Undergraduate Student (Class of 2007), Princeton University, Bethesda, MD, USA Alan J. Fischman, MD Associate Professor, Department of Radiology, Harvard University, Massachusetts General Hospital Nuclear Medicine, Boston, MA 02114, USA Michael J. Fisher, MD Assistant Professor, Department of Pediatrics, University Pennsylvania, Division of Oncology, Children’s Hospital Philadelphia, Philadelphia, PA 19104, USA

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Contributors

Marianne Glanzman, MD Clinical Associate Professor, Department of Pediatrics, University of Pennsylvania School of Medicine, Division of Child Development and Rehabilitation, Children’s Seashore House of the Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA Maria Green, RTNM Team Leader, Nuclear Medicine, Department of Diagnostic Imaging, The Hospital for Sick Children, Toronto M5G 1X8, Canada Klaus Hahn, MD Professor, Head of the Department of Nuclear Medicine, University of Munich, Ludwig-Maximilians-University of Munich, D-80336 Munich, Germany Olga T. Hardy, MD Fellow, Departments of Endocrinology and Diabetes; Children’s Hospital of Philadelphia, Core Laboratory, Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA Miguel Hernandez-Pampaloni, PhD Research Assistant Professor, Department of Nuclear Medicine, University of Pennsylvania, Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA Marc P. Hickeson, MD Assistant Professor, Department of Radiology, Division of Nuclear Medicine, McGill University, Royal Victoria Hospital, Montreal H3A 1A1, Canada Rodney J. Hicks, MB BS (Hons), MD, FRACP Professor, Department of Medicine, St. Vincent’s Medical School, The University of Melbourne, Director, Center for Molecular Imaging, The Peter MacCallum Cancer Center, East Melbourne, Victoria, Australia Robert Howman-Giles, MB BS, MD, FRACP, DDU Clinical Associate Professor, Departments of Nuclear Medicine and Pediatrics and Child Health, The Children’s Hospital at Westmead, University of Sydney, Sydney, Australia Francis Jaubert, MD, PhD Laboratoire de Anatomopathologie, Hôpital Necker-Enfants Malades, 75015 Paris, France Paul R. Jolles, MD Associate Professor, Department of Radiology, Director, Nuclear Medicine Residency Program, Virginia Commonwealth University Health System and Medical College of Virginia Hospitals, Richmond, VA 23298, USA

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Joel S. Karp, PhD Professor, Department of Radiology, University of Pennsylvania, Philadelphia, PA 19104, USA Sue C. Kaste, DO Member, Departments of Radiological Sciences and HematologyOncology, St. Jude Faculty, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA Robin Kaye, MD Assistant Professor, Department of Radiology, University of Pennsylvania, Chief, Interventional Radiologist, Children’s Hospital of Pennsylvania, Philadelphia, PA 19104, USA Geoffrey Levine, PhD, RPh, BCNP (Ret.) Associate Professor, Departments of Radiology and Pharmaceutical Sciences, University of Pittsburgh, Schools of Medicine and Pharmacy, Director of Nuclear Pharmacy, Presbyterian University Hospital of the University of Pittsburgh Medical Center, Clinical Director of the Monoclonal Antibody Imaging Center, Pittsburgh Cancer Institute, Pittsburgh, PA 15213, USA M. Beth McCarville, MD Assistant Member, Department of Radiological Sciences, St. Jude Faculty, St. Jude Children’s Research Hospital, Division of Diagnostic Imaging, Memphis, TN 38105, USA Geoffrey McCowage, MB BS, FRACP Senior Staff Specialist, Department of Oncology, The Children’s Hospital at Westmead, Sydney, Australia James M. Mountz, MD, PhD Associate Professor, Departments of Neurology and Radiology, University of Pittsburgh Medical Center, Children’s Hospital of Pittsburgh, Pittsburgh, PA 15213, USA Suzanne Munson, BA Medical Student (Class of 2007), Virginia Commonwealth University School of Medicine, Medical College of Virginia, Richmond, VA, USA Robert M. Nelson, MD, PhD Associate Professor, Departments of Anesthesiology, Pediatrics and Critical Care Medicine, University of Pennsylvania, Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA Claire Nihoul-Fekete, MD, PhD Départment de Chirurgie Infantile, Hôpital Necker-Enfants Malades, 75015 Paris, France

Contributors

Lorcan A. O’Tuama, MD Professor, Departments of Radiology, Neuroradiology, and Nuclear Medicine, Virginia Commonwealth University Health System and Medical College of Virginia Hospitals, Richmond, VA 23298, USA Christopher J. Palestro, MD Professor, Departments of Nuclear Medicine and Radiology, Albert Einstein College of Medicine, Bronx, New York, Chief of Nuclear Medicine, Long Island Jewish Medical Center, New Hyde Park, NY 11040, USA Thomas Pfluger, MD Associate Professor, Department of Nuclear Medicine, LudwigMaximilians-University of Munich, D-80336 Munich, Germany Peter C. Phillips, MD Professor, Departments of Neurology and Oncology, University of Pennsylvania, Director of Neuro-Oncology Programs, Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA Fabio Ponzo, MD Assistant Professor, Department of Radiology, New York University School of Medicine, Nuclear Medicine, New York University Medical Centers, New York, NY 10016, USA Josephine N. Rini, MD Assistant Professor, Departments of Nuclear Medicine and Radiology, Albert Einstein College of Medicine, Bronx, New York, Attending Physician Nuclear Medicine, Long Island Jewish Medical Center, New Hyde Park, NY 11040, USA Maria-João Santiago-Ribeiro, MD, PhD Service Hospitalier Frédéric Joliot, Département de Recherche Médicale Direction des Sciences du Vivant, Commissariat à l’Energie Atomique, 91400 Orsay, France Barry L. Shulkin, MD, MBA Chief, Division of Nuclear Medicine, Department of Radiological Sciences, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA Charles A. Stanley, MD Professor, Division of Endocrinology, Department of Pediatrics, University of Pennsylvania, Chief, Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA Suleman Surti, PhD Assistant Professor, Department of Radiology, Hospital of the University of Pennsylvania, Philadelphia, PA 19104, USA

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Maria B. Tomas, MD Assistant Professor, Departments of Nuclear Medicine and Radiology, Albert Einstein College of Medicine, Bronx, New York, Attending Physician Nuclear Medicine, Long Island Jewish Medical Center, New Hyde Park, NY 11040, USA Stefaan Vandenberghe, PhD Clinical Site Researcher, Philips Research, USA, Department of Radiology (PET Instrumentation Group), University of Pennsylvania, Philadelphia, PA 19104, USA Jian Qin Yu, MD Nuclear Medicine Fellow, Department of Radiology, Hospital of University of Pennsylvania, Children’s Hospital of Philadelphia, Philadelphia, PA 19107, USA Xiaowei Zhu, MS, DABMP Director, Departments of Radiology Physics and Engineering, Children’s Hospital of Pennsylvania, Philadelphia, PA 19104, USA Hongming Zhuang, MD, PhD Assistant Professor, Department of Radiology, Attending Physician, Nuclear Medicine Service, Hospital of the University of Pennsylvania, Philadelphia, PA 19104, USA

Section 1 Basic Science and Practical Issues

1 The Nuclear Imaging Technologist and the Pediatric Patient Maria Green

For the nuclear imaging technologist, success in obtaining a highquality imaging study in children is both challenging and rewarding. Imaging children for general nuclear medicine (NM) procedures requires versatile strategies that can be applied successfully to positron emission tomography (PET) imaging. This chapter discusses from the technologist’s perspective the strategies for general NM imaging, the special considerations and requirements for PET imaging, and the appropriate use of sedation in the pediatric patient. The role of the technologist is multifaceted when the focus is on imaging a pediatric patient. It is important to recognize that the technologist is working not only with a child who is anxious, frightened, or stressed, but also with parents or other family members who are anxious, frightened, or stressed. With careful planning, good communication, and some ingenuity, however, the technologist can create the right environment for a successful encounter. The goal should be to provide a quiet and friendly atmosphere with caring staff members who are calm and have a sympathetic approach and confidence in working with children. To achieve this end, it must be recognized that dealing with a child takes twice as long as dealing with an adult, and that patience is the key factor. Technologists working in a pediatric center have the advantage of working in a culture that understands the unique needs of children and their families. Established techniques used on a regular basis ensure that high-quality images are obtained and that both the patients and parents leave satisfied (1). The following should be kept in mind when dealing with the pediatric patient: the importance of communication appropriate for the child’s stage of development; the need for flexible scheduling; the appropriate injection techniques; and the imaging environment, including the use of immobilization devices or safety restraints, distraction techniques, and the possibility of sedation when absolutely necessary.

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Chapter 1 The Nuclear Imaging Technologist and the Pediatric Patient

Communication and Stages of Development Imaging children of various ages is labor intensive and quite challenging, given the unpredictable nature of a child’s behavior. A good pediatric imaging technologist should know what to expect from children at different ages, yet keep in mind that some children may be at different stages of maturity, psychosocial development, and cognitive capacity. There are many guides available that outline the various stages of child development (2). After assessing the patient by speaking with the parent and child, the technologist can effectively adjust techniques as required for the situation. Open and honest communication with parents is essential to gain cooperation and establish a good technologist–parent relationship. This can only benefit the child, who is greatly influenced by the parents’ positive or negative attitude. If at all possible, give the parents information beforehand about the procedure. Information sheets sent prior to the appointment or a phone call with preparation instructions will inform parents about what to expect. At the time of the appointment, the technologist should explain all the steps of the procedure in simple terms without using technical jargon. If the child is under the age of 8 years, the explanation should be given to the parents first. During the explanation, the technologist’s full attention should be directed to the parents and he or she should not be multitasking at the same time. Tasks such as changing linen on the imaging table or manipulating a syringe can distract the parents’ attention from the explanation. Explanations should include a reassurance about the safety of the procedure and radiation exposure, the need for the injection, timing of the images, how the imaging is done, the need for immobilization, the use of safety restraints, and other considerations necessary for the procedure such as bladder catheterization or sedation. It is also good practice to inquire about and record any medication that the child is currently taking and any known allergies. Because parents know their children best, ask them about previous experience with injections, intravenous (IV) placements, or catheterizations. Knowing how the child reacted previously or knowledge about unsuccessful IV sites can help the technologist decide on the best course of action. It is important to repeat information to parents to ensure comprehension and to allow ample opportunity for questions. Parents overwhelmed by the hospital environment and their own personal circumstances may miss key points of the explanation. The technologist must be cognizant of the fact that parents have varying levels of understanding and some have a limited history of hospital experience. Technologists must also recognize that parents can be under a great deal of stress. Not only are they coping with an ill child, worrying about the procedure and the implications of the results, but also they may have had to take time off from work, arrange for the care of other children, and deal with transportation to and from the hospital or medical center. Although infants and babies cannot understand verbal commands, they can and do react negatively to loud voices and rough handling. A

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soothing tone of voice and gentle treatment with warm hands help keep a baby from undue distress. Explanations in simple terms can be given to children starting at about the age of 3 years. Smiling to the child and using friendly facial expressions can make the child feel more at ease, as can having the child sit on a parent’s lap to feel more secure in strange surroundings. The technologist should speak directly to the child and, if at all possible, should bend or crouch to the same level so as not to be towering above him or her. Because the child may not fully understand what is being said or may not be paying attention, the technologist can emphasize the explanation by either nodding or shaking his or her head. Younger children have short attention spans, so explanations should be brief and at the child’s level of understanding. The technologist’s approach should be nonthreatening to minimize fear and apprehension (2). Children are more aware of what is going on than is generally acknowledged or appreciated, so try to be sensitive to their perception of what is happening around them. If the child appears to be frightened, ask what is frightening. It can be something totally different from what is assumed. For example, a child might be crying from a hidden discomfort or from misunderstanding a word used in the explanation. Reassure the child that you do not want to frighten him or her. Be truthful to gain a child’s trust; however, be selective about the timing of the truth. Informing a child too far in advance of an injection can result in a buildup of anxiety that can be difficult to overcome when the time for the injection finally arrives. Try to explain how the child will feel or what to expect during the injection or the procedure, but do not dwell on the unpleasant aspects. Instead, try to have the child focus on getting the injection or the procedure done quickly, emphasizing that with his or her help the task can be completed sooner. The technologist must be confident enough in dealing with a child to be in charge of all facets of the procedure. However, when the opportunity arises, the technologist may permit the child control of certain aspects by allowing the child to make some choices. The technologist can say that an injection, which is not a choice, is necessary for the test; however, if the child has several equally good injection sites, allow the child to choose one. Other examples of choices that a child can make include selecting whether to sit on a chair or on a parent’s lap, or whether to image the knees or the back first on a bone scan if the order of the spot views is not important. After an injection, ask the child if he or she would like a bandage, as a technologist cannot assume that a child will want or accept having a bandage put on. Sometimes the appearance of a bandage will signify that it is “all done,” and the child will be relieved that the injection is over; however, the child might be upset at having a bandage put on because it can be painful to remove. Crying is a very important means of communication for children. Therefore, a technologist who is working with a child must be prepared to encounter this reaction and must take control of the situation. For babies, crying is the only means of communicating that something is

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wrong and will usually stop after the cause has been remedied. A baby can be comforted after an injection, fed when hungry, or covered with a blanket when cold. Children with limited verbal skills or life experiences will cry not only from pain but also from fear and anxiety. They must not be made to feel that they are behaving badly because of their crying. This is a normal reaction to a stressful situation and should not be confused with bad behavior. Parents sometimes feel the need to control this reaction and may want to discipline the child, which only adds more stress to the already-distraught child. A prepared technologist can circumvent this situation beforehand by explaining that certain aspects of the procedure, such as an injection or a catheterization, will be unpleasant or uncomfortable. The technologist can continue to say that crying is an expected and normal reaction from the child and that it can be tolerated. Communication with school-age children is easier than with younger children, and the technologist can expect to have more of a dialogue with these children. As children get older, they are increasingly proud of their independence. Quite often, they are compliant with the technologist’s requests as long as they understand what is going on and they feel that the technologist has been honest with them. Children aged 12 to 15 appreciate being treated as an adult. However, with this age group in particular, the technologist may be dealing with opposite extremes of emotional maturity. Regardless of the patient’s age, the technologist should keep in mind that instructions and information may be misunderstood or missed with the first explanation. Taking the time to repeat key points and giving the opportunity for the parents or patient to ask questions can be very beneficial to everyone involved.

Flexible Scheduling Time is critical when dealing with the pediatric patient. Scheduling of procedures must allow for extra time and flexibility at every step in the process. As previously discussed, explanations to the parents and then to the child can be very time-consuming. Taking the time to find the optimum injection site is also very important, as a failed injection can make subsequent attempts much more difficult. The technologist must be prepared to accept that a patient injection can be as fast as 5 minutes or take as long as 30 minutes. And, finally, ample time must be allowed for the imaging procedure itself. Imaging young children for general NM procedures can often be done successfully and without sedation as long as the technologist has both the time and the patience to devote to the procedure. However, the technologist must image a child as quickly as possible to take advantage of a child’s cooperation. If too much time is taken in setting up or positioning, a window of opportunity may be lost if the child becomes restless or bored. Keeping all of these factors in mind, one can easily appreciate that it takes about twice as long to complete a procedure on a pediatric patient as on an adult.

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Injection Techniques A successful injection is paramount when performing a procedure on the pediatric patient. A failed attempt can reduce the choices of viable injection sites and further distress the child. A partially delivered dose not only causes local discomfort but also reduces the count rate for imaging, increases the imaging time, and compromises image quality. “Hot” injection sites quite often end up in the field of view, as these are difficult to move out of the way when imaging small children or babies. To ensure a successful injection, having an IV line established on the inpatient’s hospital ward prior to the procedure is the most efficient step. The technologist will only need to reassure the child there will be no pain with the radiopharmaceutical administration into the IV site. However, this is not an option for the ambulatory outpatient, and the technologist will be required to perform a butterfly needle injection or to establish an IV line. A butterfly needle affords better maneuverability and flexibility than a straight needle because the tabs or “wings” can help direct the needle into a small superficial vein more easily. Some NM procedures, such as a Meckel’s scan, diuretic washout study, or PET scan, require that an IV line is established; others require only injection by a butterfly needle. The best method of injection with a butterfly needle is to have it attached to one port of a three-way stopcock with a 10-cc syringe of saline attached to the second port, the radiopharmaceutical dose attached to the third port, and everything secured to a small injection tray to hold it all firmly in place (Fig. 1.1). Once the butterfly needle is flushed through with saline, the needle can be inserted into the vein and patency verified by saline injection into the vein. After venous patency has been established, the radiopharmaceutical dose is delivered through the butterfly needle by opening the port to the dose syringe and depressing the plunger. Once the dose has been delivered, the stopcock is turned to open the port of the saline syringe, and saline is flushed through the butterfly needle again. The technologist can continue to flush out the dose syringe with saline to ensure that the patient has received the entire amount of radiopharmaceutical. Throughout the injection, the technologist must hold the patient securely near the injection site with one hand while using the other hand to quickly and efficiently deliver the radiopharmaceutical with the butterfly-stopcock system. An assistant, such as another technologist or other health care professional, is often required to help immobilize the hand, arm, or foot that is being injected and to ensure that other limbs will not interfere. Although parents may wish to help restrain the child for the injection, this is not an optimum choice as they may either hold too hard or not securely enough to be effective. Everyone involved must be prepared for the child’s abrupt reaction to the injection, especially from a “calm” child who may not fully realize what is about to happen. Never underestimate the strength of a baby or small child when a sudden surge of adrenaline occurs during the stress of an injection. Table 1.1 lists key points for successfully injecting the pediatric patient.

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Figure 1.1. Injection tray is equipped with (1) a three-way stopcock, (2) a 10cc syringe of normal saline, (3) a butterfly needle, and (4) a shielded radiopharmaceutical dose syringe.

Table 1.1. Pediatric injection techniques: key points 1. For babies and small children good injection sites to consider are the back of the hand or the foot because these areas are easy to immobilize and the veins are more superficial (Figs. 1.2 and 1.3). 2. Use of a topical anesthetic may be of benefit to the child. However, if a young child has had a previously traumatic injection or IV experience, the child is already conditioned to expect another traumatic event and will react accordingly even though he or she may not be experiencing pain. 3. A paralyzed limb has impaired circulation, which may cause stasis of blood. 4. Dehydration may cause difficult venous access. 5. Keep in mind that for babies and small children, the tourniquet should be tight enough to restrict blood flow but not to interfere with arterial flow. While the technologist is assessing an area for veins, the tourniquet may need to be removed for a few seconds to allow the return of blood flow and then reapplied. 6. To help dilate blood vessels in a cold limb, apply a warm cloth. 7. Tap or rub the area to assist in detection of veins. 8. If an IV line is to be established, avoid using the hand of the baby’s sucking thumb. The baby may want to suck a thumb to calm down after the IV insertion, and if it is not available he or she will take longer to settle. 9. If an IV line is to be established on a baby who has equally good sites in the hands and feet, consider using the feet to allow unrestricted movement of the hand and fingers.

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Figure 1.2. The fingers and wrist are held securely in a flexed position. This technique also extends and immobilizes the vein.

Figure 1.3. The foot provides another alternative for venous access.

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Some patients have an indwelling central venous access line or port, and injection into this device may be allowed depending on the procedure ordered. Using sterile technique, the injection should be performed only by qualified personnel, and special attention must be paid to flushing the device well with saline. Failure to do so can result in radiopharmaceutical retention, resulting in a “hot spot” artifact in the chest. If the patient has symptoms or pathology in the chest, a peripheral site for injection should be used instead.

The Imaging Environment Producing the optimum environment for imaging a child requires a combination of several elements. Creating a comfortable child-friendly atmosphere, allowing a fussy baby or child to settle down, and using various methods of distraction will help the technologist to obtain high-quality images. A child-friendly room decorated with pictures on the walls (and on the ceiling above the gamma camera, if possible) helps to make the young child feel a bit more at ease and can also serve as a distraction from boredom. Removal of nonessential “scary”-looking equipment from the imaging room also reduces a child’s fear in strange surroundings. Approaching the child in a gentle, nonthreatening manner without wearing a white lab coat can help to reduce fear in a child who associates unpleasant memories with strangers in white coats. Although having toys available for a baby or young child to play with may seem like a child-friendly gesture, it is not recommended unless appropriate means are available for thorough cleaning of the toys for infection control; children of this age range readily put toys into their mouths. Instead the technologist can allow children to bring their own favorite toy or a blanket along for the scan. These items lend familiarity and comfort to strange surroundings. Placing the child’s toy on the imaging table and showing the child what the scan involves may help to reduce fear and apprehension before the child gets on the table. Allowing the child to touch the camera face can also demonstrate that the camera will not hurt him or her. For general imaging of babies and young children, selection of a single-head gamma camera, if available, is best. By positioning the camera head face up, underneath and touching the imaging table, the child can lie supine for posterior images. Not only does this allow the technologist better access to the child for immobilization and supervision, but also it eliminates the fear that a child will naturally have with the camera above him or her. This also allows the child better access to distractions such as watching a videotape. Anterior imaging can also be performed with the camera beneath the table and the child prone. However, the technologist must be meticulous with positioning, as the child might naturally want to lift his or her shoulders or keep turning his or her head. If this technique is used, the technologist must be prepared to hold any moving body parts for the duration of the acquisition.

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When acquiring anterior images with the child supine and the camera above the child, care must be taken to prevent the child from bumping his or her head on the camera. The camera should be brought down as slowly and as closely as possible without touching the child because this action will certainly terrify a young child. A single-head camera also provides more flexibility by allowing the technologist to rotate or angle the camera head for the desired view if the child is uncooperative or cannot comply with the position. It is important to continue with good communication throughout the imaging phase of the procedure. If the child is old enough to understand, it is best for the technologist either to explain in simple terms or show what is going to happen. The technologist can let the child know what is expected from him or her, such as “Lie down on your tummy” or “Keep still like a statue.” Warn the child about any noises and bed or camera motion that might occur so as not to startle him or her. Let the child know when you need to touch or hold him or her. If clothing must be removed or a diaper is to be changed, the child will feel more at ease with a parent performing that function. During a diaper change, care should be taken to wash the area thoroughly to remove any evidence of urine contamination. Allowing a parent to hold the child in the required position for an image might be comforting for the child; however, an untrained parent may not do an adequate job, and the view may need to be repeated. Repeating images only prolongs the procedure and increases the risk of losing the child’s cooperation. Speed is of the essence when dealing with the pediatric patient. Because children do not like to be restricted, it is prudent for the technologist to release the restraint as soon as the imaging is complete (3). The technologist should try to position the child as quickly and as accurately as possible, because the child’s behavior can be very unpredictable when restlessness or boredom sets in. When performing spot views for a whole-body scan, the technologist can allow the younger child to move in between the views to ward off restlessness. Saving the more difficult views (such as the anterior images with camera above the child) for the end can be a good strategy. By this time the child may have either become accepting of the procedure and surroundings or have fallen asleep. A dual-head gamma camera for whole-body imaging of children 6 years and older can be quite successful. Some exceptional 3- to 5-yearolds can also tolerate whole-body imaging or simultaneous anterior and posterior spot views. Using a videotape or DVD player with ageappropriate movies for a distraction is a definite asset to promote compliance. For single photon emission computed tomography (SPECT) procedures, children under the age of 5 years usually need to be sedated due to the length of the acquisition and their inability to remain motionless. However, having good motion correction software available for SPECT reconstruction can help the technologist salvage an acquisition with a slight amount of motion. Trying to induce natural sleep when imaging a baby or young child will yield much better results than having to restrain a wiggly child. Instructing the parents to wake their child a bit earlier on the morning

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of the procedure or having the child miss a usual nap time might work to the technologist’s advantage. For the baby who does not have to be fasting, being fed before the scan can also help to induce sleep. By dimming the lights in the imaging room and providing a quiet environment, the child might relax enough to fall asleep. However, this strategy can backfire if the child becomes overtired. Child safety is of paramount concern on the imaging table, and the use of safety straps is strongly recommended (Fig. 1.4). The technologist must always explain to the parent and child the need for the safety strap before putting it on. A child should never be left unattended while lying on an imaging table, and a busy technologist can enlist the help of a parent to stay beside the child when the technologist must leave the room. At the completion of the scan, it is prudent for the technologist to keep the child on the imaging table until the study has been checked. It is sometimes very difficult to have children return to the imaging table for more images once they have been allowed off (3). Another challenge for the technologist is to ask a toilet-trained child to void. Children may see this as a choice that they can make, and uncooperative children can seize the opportunity to control the circumstances by refusing to void. Instead of asking, the technologist should tell the child that he or she must void before the test can begin, using words that are suitable to the child’s level of understanding. The parents can advise the technologist which phrases or words are used at home for the younger, newly toilet-trained child, such as “go potty” or “pee.” If the child does not feel the urge to void, encourage him or her to try anyway. It is best not to pressure the child, as this can soon become a power struggle among the child, parent, and technologist. Depending on the procedure, if the child cannot or will not void, the technologist must decide whether to continue with the scan and try to eliminate the bladder activity with lead shielding or with software

Figure 1.4. A safety strap, along with direct adult supervision, should always be used when a child is lying on the imaging table.

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removal or wait until the child can comply by voiding. As a last resort, and with the referring clinician’s consent, catheterize the bladder. Because telling a baby or non–toilet-trained child to void is not an option, the technologist must be prepared to wait for the infant to void spontaneously; or, if the procedure requires it, catheterize the bladder. Having the child listen to the sound of running water from a tap or pouring warm water over the child’s perineum may have limited success in stimulating bladder emptying. If these alternatives are not possible, techniques such as software removal of bladder activity or imaging with a lead shield overlying the bladder can be helpful. To help build a good technologist–patient relationship, words of encouragement and praise can be given. If the child’s efforts to hold still for the images or cooperate for the injection are recognized, the child will feel more involved and have greater self-esteem. Tokens of appreciation such as stickers given to the child at the end of the procedure are usually well received and sometime distract the child from any unhappy memories. Giving candies is strongly discouraged. However, if this type of reward is considered, the technologist must discreetly check with a parent first.

PET Imaging and the Pediatric Patient Improvements in PET and PET/computed tomography (CT) technology that have resulted in increased image quality and decreased acquisition time have made PET imaging possible for routine pediatric applications. By utilizing the strategies and techniques used for general NM procedures, as previously discussed, PET imaging can be successfully tolerated by children. This section focuses primarily on PET and PET/CT imaging using fluorine-18 fluorodeoxyglucose (FDG) for whole-body oncology studies. Special attention is given to patient preparation, including fasting and glucose levels, FDG administration, FDG uptake phase, and other technical considerations specific to PET and PET/CT imaging. Patient Preparation Communication continues to be one of the most essential steps for patient preparation. As discussed earlier, information about the procedure should be given to the parents beforehand, either by information sheets sent prior to the appointment or by a phone call with preparation instructions. Parents can be confused by the very complex nature of FDG-PET or PET/CT imaging, and ample time must be allotted to explain the study and to allow the parents an opportunity to ask questions. For children undergoing a PET or PET/CT scan, this may not be their first experience in a nuclear medicine or CT department. They may have been examined previously as part of the initial diagnostic workup. If this is the case, a good technologist–patient/parent relationship may already have been established.

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If no anesthetic will be used and there is sufficient time, the technologist should show the child the scanning room to describe how the scan will be performed. Key points to cover include the steps involved in the procedure, the need for an IV line and possible bladder catheterization, estimated time for each sequence, and the expectation of keeping the child inactive during the FDG uptake phase. To ensure that the fasting instructions have been followed, the technologist should take careful note about when the child last had something by mouth, including candies, gum, or any glucose-containing liquids or medications such as cough syrup; also take note of what the child ingested. All of the above should be discussed prior to the FDG injection in order to reduce the technologist’s exposure to the high-energy photons of 18F. Because FDG is excreted by the kidneys, urine retention in the bladder can cause many difficulties with reconstruction and image interpretation. To eliminate these problems, bladder catheterization may be necessary. However, the timing of the bladder catheterization can be problematic. Ideally, the catheter should be inserted after an IV line has been established. Not only will this allow the child time to calm down prior to FDG administration, it also will further reduce the technologist’s radiation exposure and avoid the possibility of urine contamination on the patient. If sedation is required for the scan, the child should be catheterized beforehand, because sedation does not eliminate the pain response and the child could become agitated (4,5). If general anesthesia is to be used, the child will not feel any pain and may be catheterized just prior to imaging after the induction of anesthetic. However, when catheterizing the child, one must work carefully and efficiently to avoid urine contamination and to keep radiation exposure of the catheterizing personnel to a minimum. To reduce urinary retention in the upper tracts, administration of a diuretic may be considered if clinically appropriate (6). Fasting and Glucose Levels The same mechanism that makes FDG a desirable radiopharmaceutical to image glucose metabolism in tumors creates many challenges for the technologist and parents with respect to fasting and activity restrictions. Fasting is crucial prior to FDG injection so as to reduce glucose utilization and lower circulating insulin, thereby optimizing the target to background ratio (7). Whenever a baby or young child is kept fasting, predictably stress levels increase for parents, because a hungry child is also an unhappy child. The length of time fasting can vary from 4 hours for infants (8) to 6 to 8 hours for the older child (6). Most oral medications, if glucose-free, can be taken with water during the fasting period. Thirty minutes after injection, infants can be fed or a thirsty child can have some water (8); however, if sedation or general anesthesia is to be used, the child must remain fasting. If oral contrast is required, it can be given in a glucose-free liquid at the appropriate time prior to the CT (7). Administration of oral contrast prior to PET acquisition does not significantly complicate image interpretation (4).

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Following fasting, some imaging centers assume stabilized blood glucose levels, whereas other centers take an actual measurement using a glucometer or obtain a serum glucose level from the laboratory to ensure the level is £150 mg/dL prior to FDG injection. For the diabetic child, management of blood glucose levels may require consultation with a diabetic-control specialist (6,7). If the child is receiving intravenous fluids containing dextrose or total parenteral nutrition (TPN), the dextrose in the solutions will compete with the FDG uptake. So as not to compromise the PET study, administration of these fluids should be suspended for 6 hours prior to FDG injection (7). Fluorodeoxyglucose Administration The recommendation for pediatric use is 5 to 10 MBq/kg or 0.15 to 0.30 mCi/kg with a minimum dose of 37 MBq or 1 mCi (5). There appears to be no contraindication for FDG administration (9). Although a successful injection is paramount in performing a general NM imaging procedure, it is more so for PET imaging. A “hot” injection site in the field of view can cause an artifact on reconstruction, and dose extravasation can result in lymph node uptake. Both situations may hinder the interpretation of the scan. A failed injection also increases the cost of performing the study, because the price of FDG is very expensive and the child may need to be rescheduled to another day. Rescheduling the child’s PET scan not only delays provision of diagnostic results to the referring clinician but also increases parental stress and anxiety because the child will have to undergo the preparation and injection all over again. It has been reported that FDG injection into indwelling central venous lines/ports followed by thorough flushing with saline is acceptable (4,6). However, unless there is absolutely no other alternative, it is highly recommended to establish an IV line in a peripheral site instead. This action prevents possible radiopharmaceutical retention in the central line/port and interference on the scan. Furthermore, if the child requires intravenous contrast for a CT, a peripheral IV line may be necessary, as many centers do not use a power injector into a central line/port. To ensure a successful injection, having an IV line established on the inpatient’s hospital ward prior to the procedure is the most efficient step. The technologist will need only to check for venous patency and can reassure the child that there will be no pain with the radiopharmaceutical administration into the IV site. However, for the ambulatory outpatient, the technologist will need to establish an IV line and allow time for the child to calm down. Having the patient in a calm and relaxed state will minimize muscle uptake caused by excessive movement or muscle tension, both of which are likely to occur when a child has a needle injection. A butterfly needle is not recommended for FDG injections, as using a secure IV line will allow quick and successful delivery of the FDG, which will also reduce the technologist’s radiation exposure.

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Fluorodeoxyglucose Uptake Phase Another challenging aspect of performing PET imaging in a child is the restriction of physical activity to minimize the uptake of FDG by the muscles. Physical activities such as muscle stress, tension, movement, or even talking increase muscle uptake, and trying to restrict these activities for a child can be difficult. To facilitate this goal, a quiet, dim room should be used for the child to rest, either in a lounge chair or on a comfortable stretcher, for at least 20 to 30 minutes, with imaging commencing about 60 minutes after injection (6). The room should be equipped with appropriate support equipment including a sink, oxygen, suction, and a restroom facility close by (7). The parents must understand the importance of inactivity during this phase and help to ensure minimal stimulation. The child can rest comfortably watching a quiet videotape or DVD movie, listening to soft music, or having a parent read to him or her. To reduce the radiation exposure to the parents, it is recommended that only one (nonpregnant) parent remain with the child for the duration of the uptake phase. Using a monitoring camera in the uptake room is a practical way for the technologist to supervise the child’s status remotely. This serves two purposes, as the technologist will not have to disturb the quiet environment to check on the child and he or she will avoid additional radiation exposure. Other means of reducing muscle uptake of FDG in certain situations include the use of muscle relaxants (6), which can also help calm an anxious or claustrophobic child, and sedation or general anesthesia. However, the length of time that a child would need sedation or general anesthesia for both the uptake and scan phases would be considerable. If resources are limited, the logistics for this course of action can be difficult, as monitoring by qualified personnel is required for both phases. During the uptake phase, the child should be kept warm in order reduce the uptake of FDG in brown fat that can interfere with image interpretation (7). This can be accomplished by keeping the ambient temperature of the uptake room warm or by wrapping the child in heated blankets. PET and PET/Computed Tomography Imaging When the FDG uptake phase is over, the child must void just before entering the scanning room. This will eliminate the bladder activity from the images and ensure the child’s bladder comfort for the duration of the lengthy scan. If the child has been catheterized, the technologist must position the drainage tube to keep the bladder continuously drained and to avoid overlapping the tube with the body. Once in the room, the technologist can reassure the child that there will be no loud noises during the scan and continue with reassurances that although the scanner will never touch the child, for safety purposes a safety strap or restraint will be used. To reduce the risk of motion due to discomfort, the technologist can be creative and use various cushions, straps, and tape to keep the child in position for the study (8). To help ward off boredom, the child can listen to a music or

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storybook audiotape. If the head is not being imaged, watching a videotape or DVD can also be an option. For whole-body imaging, the child is positioned with arms down, using the safety strap wrapped around the arms and torso to secure them in place. The technologist must pay special attention to having the child lying flat and not rotated so that the body will appear symmetrical in the reconstructed images. For patient safety and comfort, the technologist must make sure that any intravenous or catheter lines, oxygen tubing, straps, sheets, and monitoring equipment are safely arranged to allow free motion into and out of the scanner. Situating the child with his or her head out of the scanner as much as possible helps to reduce fear or claustrophobia. For the noncatheterized child, the pelvis should be imaged first to minimize the effects of the bladder filling; therefore, the imaging sequence can start with the pelvis and legs and move to the torso and head (5,6). Attenuation correction for PET images is essential and can be obtained either by transmission imaging in a conventional PET scanner or by utilizing CT in a PET/CT scanner. For conventional PET, transmission images are obtained using a rotating rod source. The transmission scan (3 minutes per bed position) is acquired before the emission scan (4 to 7 minutes per bed position) (4,10). Therefore, a 60-cm, two-level (bed position) emission-transmission scan can be obtained in approximately 20 minutes. The number of bed positions and total acquisition time required for the study vary according to the size of the child, and the imaging procedure may take up to an hour. With PET/CT technology, attenuation correction is obtained using spiral CT, which can be acquired in less than a minute. The patient is imaged from top to bottom. At completion, the child is ready to start the emission scan at the level of the pelvis in order to avoid the bladder activity. With an emission scan imaging typically lasting 5 minutes per bed position, a 60-cm, two-level study can be acquired in about 11 minutes (4). Throughout the entire PET/CT procedure, the technologist, along with other personnel (such as a radiologist, nurse, or anesthesiologist if required), stay in the adjacent control room where the patient can be viewed through leaded glass; with an additional camera monitoring system, a closer view of the child can be obtained. This system is especially useful when a child is monitored while under sedation or anesthesia. Words of encouragement and support can be given to the child through a microphone during the scan. As the scan nears completion, informing the child that only a few minutes are left can help to maintain cooperation. Following the PET scan, a diagnostic CT may also be ordered. The child may need to move his or her arms to an upright position if a CT is performed with the PET/CT scanner. However, for some complex CT protocols, the study may need to be done using a devoted CT scanner with CT technologists (4). At the end of the emission-transmission or CT-transmission scans, the technologist reviews the acquired images to check for patient

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motion and completeness of the study. If all is in order, the child can leave the scanning room. If sedation or a general anesthesia has been used, the child will go to a recovery room until he or she can return to the hospital ward if an inpatient, or be discharged to go home if an outpatient. If sedation has not been given, the technologist or a nurse can take the child to a treatment room to remove the IV line and catheter (if used). Taking the child to another room for the removals serves many purposes. After leaving the scanning room, the child will finally feel that the procedure is done, and once the scanning room is vacant, preparation for the next patient can begin. Removal of an IV line or catheter can be time-consuming, and there is no need to occupy the scanning room for that purpose. Also, removing the catheter in another location other than the scanning room precludes the possibility of urine contamination on the imaging table. As previously mentioned, the technologist should ask the child first if he or she would like a bandage after the IV line is removed. Again, words of encouragement and praise given for recognition of the child’s cooperation will elevate his or her self-esteem and help to develop a good technologist–patient relationship. Stickers given as tokens of appreciation at the end of the procedure are usually well received and can divert the child from unpleasant memories. Because oncology patients return frequently for PET studies as part of their treatment, the technologist must realize that actions taken today may influence how the child and parents will react on the next appointment. In this sense technologists should consider themselves “goodwill ambassadors” and try to make the child’s experience as positive as possible.

Sedation: The Technologist’s Perspective Sedation in the pediatric patient should never be used routinely but should be considered on an individual basis only. Most general nuclear medicine procedures can be performed without sedation and yield excellent results using the previously mentioned strategies. Many situations can be managed successfully by the technologist without sedation, as shown in Table 1.2. However, children of ages 8 months to 4 years require total immobilization by sedation for procedures such as bone scans, SPECT, and PET (11). Once it has been decided that sedation will be used, the technologist must involve other professionals in the administration, continuous monitoring, and recovery following the procedure. Guidelines and methods vary according to different departments and institutions, and the technologist must confirm that the required sedation preparation instructions have been followed before the child is injected for the scan. If a contraindication for sedation or discrepancy with preparation has been discovered, the sedation and scan should be postponed to another day. The technologist must communicate concisely with all involved individuals throughout the procedure to minimize any confusion and ensure a successful study.

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Table 1.2. Alternatives to sedation Situation Child crying from having an injection

Alternative • This is a normal and expected reaction from a child. A topical anesthetic can be applied; however, this will not eliminate a conditioned response to fear. • Once the injection or IV line has been established, reassure the child that all the “hurting” is finished. • Quickly distract the child’s attention to more pleasant thoughts, such as going home, talking about a pet, or watching a videotape or DVD.

Child’s restlessness during a lengthy scan

• Use distractions mentioned above. • If possible, allow the child to move or stretch between different images. • Have the child count down to the end of the acquisition, e.g., five, four, three, two, one—all done! • Try to induce natural sleep. If the child has been sleep deprived and cried a lot during the injection, he or she will be tired. Make the child comfortable, keep the area as quiet as possible, and dim the lights. • If fasting is not required, feeding the child prior to imaging can also induce natural sleep.

A parent’s fear of the procedure

• Provide excellent communication about what the procedure involves and the expected reaction from the child. • Reassure the parent that a successful scan is possible without using sedation.

A parent’s preconceived notion that the child is not capable of cooperating

• Often a child will react differently to a stranger’s request and comply with the scan. • In some extreme situations, the technologist might ask the parent to leave the room. Once the parent is out of sight, the child may comply with the technologist because the child is no longer trying to control the parent.

Conclusion Many unique and challenging issues must be considered when a nuclear imaging technologist is involved with a pediatric patient. Working with children requires patience, an active imagination, honesty, and flexibility. By adopting the techniques and strategies discussed in this chapter, the technologist can be confident that a highquality study has been obtained and satisfied that the child and parent have had a successful and smooth encounter in the nuclear medicine department.

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References 1. Gordon I. Issues surrounding preparation, information and handling of the child and parent in nuclear medicine. J Nucl Med 1998;39:490–494. 2. Veitch T. Pediatric nuclear medicine, part I: developmental cues. J Nucl Med Technol 2000;28:3–7. 3. Veitch T. Pediatric nuclear medicine, part II: common procedures and considerations. J Nucl Med Technol 2000;28:69–75. 4. Roberts E, Shulkin B. Technical issues in performing PET studies in pediatric patients. J Nucl Med Tecnol 2004;32:5–9. 5. Hossein J, Connolly L, Shulkin B. PET imaging in pediatric disorders. In: Valk P, Bailey D, Townsend D, et al., eds. Positron Emission Tomography: Basic Science and Clinical Practice. London: Springer-Verlag, 2003:756. 6. Hamblen S, Lowe V. Clinical 18F-FDG oncology patient preparation techniques. J Nucl Med Technol 2003;31:3–10. 7. Kaste S. Issues specific to implementing PET-CT for pediatric oncology: what we have learned along the way. Pediatr Radiol 2004;34:205–213. 8. Borgwardt L, Jung Larsen H, Pedersen K, et al. Practical use and implementation of PET in children in a hospital PET centre. Eur J Nucl Med Mol Imaging 2003;30:1389–1397. 9. Kapoor V, McCook B, Torok F. An introduction to PET-CT imaging. Radiographics 2004;24:523–543. 10. Czernin J, Schelbert H. PET/CT imaging: facts, opinions, hopes and questions. J Nucl Med 2004;45:1S–3S. 11. Pintelon H, Jonckheer MH, Piepz A. Paediatric nuclear medicine procedures: routine sedation or management of anxiety? Nucl Med Commun 1994;15:664–666.

2 Sedation of the Pediatric Patient Robin Kaye

Imaging pediatric patients provides many interesting challenges, not the least of which is keeping them motionless for the studies. Almost any imaging study is degraded, to a greater or lesser degree, by patient motion, and this can be particularly true for nuclear medicine studies where spatial resolution is an issue. Unfortunately, even the most cooperative child often cannot hold still for an imaging study of any length. This means that adequate sedation is one of the most important factors in performing high-quality imaging studies in children. This chapter discusses some of the basic concepts in pediatric sedation and suggests an approach to providing safe and effective sedation of children who are referred for PET scanning.

Background In 1992 the American Academy of Pediatrics (AAP) revised its Guidelines for Monitoring and Management of Pediatric Patients During and After Sedation for Diagnostic and Therapeutic Procedures (1) and defined the goals of safe pediatric sedation. Other organizations, such as the American Society of Anesthesia (ASA) and the American College of Radiology (ACR), have also written such standards. In 2002 the ASA revised its practice guidelines for sedation and anesthesia by nonanesthesiologists (2), and in 2005 the ACR revised its guidelines for sedation of pediatric patients (3). The Joint Commission on Accreditation of Healthcare Organizations has adopted the concepts provided by the AAP guidelines, which has become a template for institutional policies and procedures for pediatric sedation in hospitals throughout the United States (4). The primary goal for sedation in the pediatric patient, as defined in these guidelines, is to guard the patient’s safety and wellness in order to avoid sedation accidents. In addition to patient safety, successful sedation of pediatric patients also has the goals of minimizing physical discomfort or pain, controlling behavior, minimizing negative psychological responses, and 21

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returning the patient to a state in which safe discharge is possible. All clinicians and support staff involved in the sedation of pediatric patients should understand and follow these guidelines. Further, it is highly advisable that, in order to ensure safe sedation of the pediatric patient undergoing imaging, a unified approach should be used in the radiology department and indeed throughout the entire institution (2,5–9) to help avoid errors that could potentially lead to sedation accidents. To ensure that each of these goals is accomplished, several steps must be taken. First, the patient’s present and past medical and surgical history must be thoroughly evaluated to find any possible problems that could affect sedation (Table 2.1). Second, the patient should be fasting from solids (including formula or milk), breast milk, and clear liquids for an adequate period of time. Neonates and infants under 6 months of age should be NPO (nothing by mouth) for 2 hours for clear liquids, for 3 hours for breast milk, and for 4 hours for solids. Patients from 6 to 36 months of age should be NPO for 2 hours for clear liquids, for 3 hours for breast milk, and for 6 hours for solids. Patients over 36 months of age should be NPO for 2 hours for clear liquids and for 6 to 8 hours (at the physician’s discretion) for solids. This regimen is recommended to decrease the risk of aspiration during sedation (Table 2.2). The only exception to these guidelines should be for those patients who require an oral medication, such as an antiseizure drug. These drugs are given prior to the procedure with small sips of water or other clear liquid at least 2 hours prior to the procedure. Third, the sedation should be planned ahead of time, ideally based on a sedation protocol that includes a drug formulary that is comprehensive and appropriate for children of all ages and conditions. The appropriate sedative agents should be selected and doses calculated on a milligram per kilogram (mg/kg) basis, with a full understanding of

Table 2.1. Risk factors for sedation Respiratory Cardiovascular Neurologic Gastrointestinal Genitourinary Systemic/other Syndromic

Pneumonia, chronic lung disease, asthma tracheo- or bronchomalacia, sleep apnea, mediastinal mass Cyanotic heart disease, congestive heart failure (CHF), hypotension, cardiomyopathy Seizures, central respiratory depression Gastroesophageal reflux disease (GERD), hepatic dysfunction/failure Renal dysfunction/failure, dehydration, electrolyte disturbances Sepsis, allergies, medications, low hemoglobin Macroglossia, micrognathia, chest wall deformity, craniofacial deformity scoliosis

R. Kaye

Table 2.2. Risk factors for pulmonary aspiration of gastric contents History of recent oral intake Extreme obesity Pregnancy Patients with abnormal airway anatomy Neurologic disorder Neurologic dysfunction Head trauma Deceased level of consciousness Gastrointestinal disorders Bowel motility dysfunction Esophageal dysfunction Gastroesophageal reflux Gastrointestinal obstruction Prior esophageal surgery Previous administration of pharmacologic agents Drugs that decrease gastric motility Drugs that produce loss of consciousness or depressed level of consciousness Drugs that produce loss of or reduce protective airway reflexes

their pharmacokinetics and pharmacodynamics. The selected agents should be titrated to effect, and sufficient time should be allowed to elapse between doses to achieve peak drug effect before administration of additional drugs. The doses of any pertinent reversal drugs should also be calculated ahead of time, although it is not necessary to have them drawn up for the procedure. Fourth, if sedations are going to be performed, it is imperative to have high-quality monitoring equipment appropriate for all ages and sizes of children and an adequately trained group of sedation nurses with the knowledge and skills to properly monitor the patient during drug administration and during the procedure. Patients should also be monitored postprocedure to ensure that they are fully recovered from the effects of sedation before being released from medical supervision. Fifth, there must be readily available resuscitation carts with medications and a full range of functioning age- and size-appropriate equipment, such as laryngoscopes, endotracheal tubes, oral airways, bags, and masks, to manage emergencies. One further precaution is the need for staff members to recognize their own limitations in experience and expertise; in those instances when the experience and expertise of the available staff are not sufficient, it is prudent to reschedule the examination for sedation by an anesthesiologist or other sedation specialist (Table 2.3).

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Table 2.3. Circumstances that may require the assistance of an anesthesiologist or other specialist in sedation Patient factors ASA class III or higher History of severe emotional or psychiatric illness History of major allergy or anaphylactic reaction Morbid obesity Sleep apnea Pregnancy Chemotherapy-induced cardiomyopathy Anatomic airway abnormalities Life-threatening underlying medical/surgical conditions History of difficult sedations Patients with a full stomach Patients with significant cardiac, pulmonary, renal, or central nervous system (CNS) dysfunction Procedural factors Prolonged sedation Complex procedure New procedure Emergency procedure Procedure and patient suitable for regional block Procedure carried out in unusual position or geographic location Miscellaneous factors Skilled personnel not available Inadequate facility or equipment

Levels of Sedation Sedation is on a continuum from consciousness to unconsciousness and is a dynamic process. In children, in particular, progression along this continuum can be imperceptible and rapid, and may not depend so much on actual drugs and dosages but rather on individual responses. Because the level of sedation prescribes the intensity of monitoring, the team performing the sedation must be prepared to assess the true level of sedation and be prepared to increase the level of monitoring accordingly. There are three commonly described levels of sedation: conscious sedation, deep sedation, and general anesthesia. The differences between each of these levels should be well understood (Table 2.4). Conscious sedation is defined as a medically controlled state of depressed consciousness in which protective reflexes are maintained, including the ability to maintain a patent airway and the ability of the patient to respond appropriately to verbal or physical stimuli. A true state of conscious sedation can be very difficult to attain in children. In our experience, most children require a deep level of sedation during procedures. Observation and monitoring of the pediatric patient who is medicated for conscious sedation includes continuous pulse oximetry, heart rate, intermittent respiratory rate, and blood pressure monitoring by a trained observer who frequently evaluates the patient but who may also participate in the procedure.

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As compared to conscious sedation, deep sedation is a medically controlled state of depressed consciousness or unconsciousness in which the patient is not easily aroused and does not respond purposefully to verbal or physical stimuli and in which the patient may or may not maintain protective reflexes, including keeping a patent airway. In general, sedation protocols commonly used in radiology departments only very infrequently result in airway compromise. Monitoring for patients under deep sedation is significantly more intense than for those who are under only conscious sedation, as would be expected. The patient must have a working intravenous (IV) line; pulse oximetry and heart rate are continuously monitored; and vital signs (blood pressure, heart rate, and respiratory rate) are recorded every 5 minutes by an independent practitioner whose sole responsibility is to observe the patient’s vital signs, airway patency, and adequacy of ventilation. Resuscitation equipment and medications must be readily available. General anesthesia is a medically controlled state of unconsciousness in which protective reflexes are lost, the airway cannot be independently maintained, and the patient cannot respond to verbal or physical stimuli. Only specially trained physicians, or nurse anesthetists under their direct supervision, can provide general anesthesia. The choice of whether to use sedation or general anesthesia is influenced by many factors: the physician’s experience and expertise with sedation techniques and drugs, the ASA status of the patient, the availability of nurses trained in sedation techniques and patient monitoring, the institutional policy regarding sedation, and the length, complexity, and risk of the procedure to be performed. The risk of sedation-related complications increases directly or even exponentially with increasing ASA status (10). In general, patients with ASA I or II status are well suited for IV sedation by a radiology sedation team. Children with ASA class III status should be carefully evaluated and their condition and attendant risk factors carefully understood by the radiology sedation team before attempting IV sedation. ASA class IV status patients are most suitably cared for by an anesthesiologist or intensivist. Table 2.4. Levels of sedation Conscious sedation Deep consciousness

Deep sedation Deep consciousness/ unconsciousness

General anesthesia Unconsciousness

Protective reflexes maintained

Protective reflexes may or may not be maintained

Loss of protective reflexes

Patent airway maintained independently

+/- Ability to maintain patent airway independently

Inability to independently maintain patent airway

Appropriate responses to verbal or physical stimuli

Inability to respond to verbal or physical stimuli appropriately

Inability to respond at all to verbal or physical stimuli

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In addition, when there is a history of failed sedation, or when extreme patient cooperation is required, general anesthesia should be used.

Approach to Sedation In our opinion any radiology department doing five or more cases per day that require medication to facilitate quality imaging should consider developing a sedation program. Performing that volume of cases using general anesthesia would be extremely challenging because, in our experience, most cases take at least 1.5 hours to complete. Sedation by a radiology sedation team is preferred whenever possible because it allows easier, faster, and more flexible case planning and preparation and is less costly than general anesthesia. When sedation is chosen, formal protocols for preprocedural, intraprocedural, and postprocedural monitoring of the patient are imperative. Although it is beyond the scope of this chapter to review all of the possible drugs that may be used, alone and in combination, to sedate children, I would like to describe the approach to sedation used by my department. We have used this method successfully and safely for many years, and although it is not the only approach that can be used, it is a time-tested one that can easily be adapted to use in a variety of settings. We use three main classes of agents for pediatric sedation: anxiolytics, barbiturate sedatives, and opioid analgesics. It is not important to know about all of the drugs available in each category. What is important is to choose a few of the drugs from each category and be familiar with their dosing, pharmacokinetics, and pharmacodynamics (e.g., time to peak effect, duration of action, and route of elimination), side effects, interactions with other sedative agents, and reversal agents (if any are available). Having a small, stable formulary that is familiar and predictable enhances the safety and effectiveness of the sedation program. To successfully sedate children for the purposes of imaging or interventional procedures, the sedation team must carefully create a safe environment. In our opinion, safe and effective sedation facilitated by a team approach requires the presence of experienced pediatric radiology nurses, and in our practice we work very closely with these nurses. The radiology nurse is not only involved in obtaining pertinent information about medical history and physical examination, confirming preprocedure laboratory results, and acting as a liaison with the physicians and nurses caring for the patient in the hospital, clinic, or outside facility, but also dispenses sedation medications and monitors and records the patient’s condition during and after sedation. It is these nurses who provide the backbone and consistency for an excellent sedation program. It is our preference to select nurses who have experience in an intensive care unit, pediatric transport, emergency room, or other area that cares for acutely ill children. However, nurses without this experience may also work well on a sedation team if they are trained and mentored to recognize and assess children who

R. Kaye

are at risk for problems and complications and take action when necessary. Our approach to sedation is similar for diagnostic imaging or interventional procedures. As a rule we use single drugs, or two or more drugs in combination, that have the fastest time to action, the fewest untoward effects, and the shortest half-life, so that the return to baseline is as fast as possible. This approach enables us to discharge the patient to home or to the inpatient unit in the shortest time. Also, if untoward effects occur, they are as brief as possible. We divide patients into two groups based on age: patients 1 year of age or less and patients who are older than 1 year. In children who are 1 year of age or less, the primary sedative is chloral hydrate. This drug may be given either by mouth or per rectum as a suppository. We rarely use the drug per rectum because of its variable absorption and less reliable onset of action. In children 3 months of age or younger we usually begin with a dose of 50 mg/kg and in those older than 3 months of age we start with a dose of 75 mg/kg (or 1 g maximum single dose). In either group, the maximum total dose is 100 mg/kg or 1 g. The most common adverse effects of chloral hydrate are respiratory depression and occasionally hypotension. Chloral hydrate has no reversal agent and has a relatively long and somewhat unpredictable time to action, approximately 20 to 30 minutes, which is an obvious drawback. If the patient is not asleep in 20 to 30 minutes after the initial dose, one may want to consider giving a second dose of chloral hydrate or giving a second drug. Usually the determining factor in clinical practice is whether the patient has a functioning IV in place. Those children without IVs often receive a second dose of chloral hydrate, usually 25 to 50 mg/kg (again with a maximum total dose of 100 mg/kg or 1 g). Those patients who have a working IV may benefit from the addition of either Versed (0.05–0.1 mg/kg) or fentanyl citrate (1 mg/kg) to augment the sedation. In some cases in this age group, especially for short studies, a combination of Versed and fentanyl alone, given intravenously in the doses mentioned above, can also be used very successfully. Children older than 1 year are most commonly sedated with a combination of intravenous drugs. Because anxiety is very frequently a part of the child’s response to being in the hospital and to imaging studies, we almost always start with a dose of Versed, a benzodiazepine used frequently for anxiolysis, in doses of 0.1 mg/kg (or 3 mg maximum single dose). This drug has the added benefits of creating antegrade amnesia in most patients and of producing mild sedative effects. We have found that when the patient’s anxiety level is reduced by the use of Versed, the sedation is smoother and the total dose of sedation medication is often less, thereby reducing recovery time, and the overall experience for the patient (and the parents) is much less traumatic. We administer the Versed 1 to 5 minutes before giving our primary sedative agent. The most common adverse effects of Versed are doserelated respiratory depression and occasionally paradoxical agitation.

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Versed can be reversed by flumazenil in doses of 0.01 mg/kg to a maximum of 0.2 mg, but the patient needs to be carefully observed for re-sedation. Our primary sedative agent is pentobarbital sodium (Nembutal). We use 3 mg/kg (or 100 mg maximum single dose) with a fast IV push as our initial dose. Although pentobarbital is an excellent and safe sedative, it has the undesirable property of creating hyperesthesia, and it has a long half-life leading to a relatively long time to return to presedation baseline. The most common adverse effects of pentobarbital are respiratory depression and occasionally emergence delirium. Pentobarbital has no reversal agent. To reduce the hyperesthesia effect and potentially reduce the total dose of pentobarbital needed, fentanyl citrate, a short-acting narcotic, can be added in doses of 1 mg/kg (or 50 mg maximum single dose) within minutes of giving pentobarbital. The most common adverse effects of fentanyl are respiratory depression and transient hypotension. Fentanyl can be reversed by naloxone in 0.01 mg/kg for children and 0.4 to 2 mg for adults, repeated as necessary, but the patient needs to be carefully observed for re-sedation. With this combination of three drugs, the vast majority of children will be sedated adequately to perform the diagnostic imaging study that is planned. If, after these drugs are initially administered the child is still moving, more drug or the addition of another drug is needed. The drug selected depends on the clinical state of the child. If the child is awake (eyes open, talking) a repeat dose of pentobarbital at 2 to 3 mg/kg is given. If the patient is responding to noise, touch, or other stimuli without awakening, an additional dose of 0.1 mg/kg of Versed and/or 1 mg/kg of fentanyl citrate is given. Depending on the patient’s status and the clinical situation, if the patient has been given two full rounds of drugs and is not adequately sedated, then there should be careful consideration given as to whether to administer a third round of drugs or to abandon the procedure and call a failed sedation. The maximum total doses that we use in most diagnostic settings are 7 mg/kg (or 300 mg) for pentobarbital, 3 mg/kg (or 150 mg) for fentanyl, and 0.3 mg/kg (or 5 mg) for Versed. It should be remembered that the respiratory depressant effects of all three of the drugs used in this regimen are potentiated by one another and are additive. This requires rigorous monitoring of the patient and immediate treatment of any evidence of respiratory depression as soon as it is recognized. It is also important to remember that to maximize safety, fentanyl should always be diluted and injected slowly or added to the fluid in the drip chamber of the IV infusion set and dripped in slowly, over about 1 minute, to avoid severe respiratory depression, apnea, or the feared complication of “wooden chest syndrome.” This syndrome of chest wall rigidity is a phenomenon during which the patient’s chest wall muscles become spastic, making ventilation extremely difficult. Although the exact mechanism of these muscle contractions has yet to be identified, many authors have described success in reversing chest wall rigidity with either naloxone (Narcan) or muscle relaxants such as succinylcholine, with rapid resolution.

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References 1. American Academy of Pediatrics. Committee on drugs: guidelines for monitoring and management of pediatric patients during and after sedation for diagnostic and therapeutic procedures. Pediatrics 1992;89: 1110–1115. 2. American Society of Anesthesiologists Task Force on Sedation and Analgesia by Non-anesthesiologists. Practice guidelines for sedation and analgesia by non-anesthesiologists. Anesthesiology 2002;96:1004–1017. 3. Towbin RB, Cardella JF, Barr JD, et al. ACR Practice Guideline for Pediatric Sedation/Analgesia. ACR Guidelines and Standards Committee of the Interventional and Cardiovascular Radiology Commission, Practice Guidelines and Technical Standards, Reston, VA. 2005:427–433. 4. Policy and Procedure for Intravenous Conscious Sedation. JCAHO Manual 1996:84–135. 5. Hoffman GM, Nowakowski R, Troshynski TJ, et al. Risk reduction in pediatric procedural sedation by application of an American Academy of Pediatrics/American Society of Anesthesiologists process model. Pediatrics 2002;109:236–243. 6. Holzman RS, Cullen DJ, Eichhorn JH, Philip JH: Guidelines for sedation by nonanesthesiologists during diagnostic and therapeutic procedures. The Risk Management Committee of the Department of Anaesthesia of Harvard Medical School. J Clin Anesthesiol 1994;6:265–276. 7. Guidelines for the elective use of pharmacologic conscious sedation and deep sedation in pediatric dental patients. Pediatr Dent 1993;15:297–301. 8. American Academy of Pediatrics. Committee on drugs: guidelines for monitoring and management of pediatric patients during and after sedation for diagnostic and therapeutic procedures: addendum. Pediatrics 2002;110:836–838. 9. Coté CJ: Sedation protocols—why so many variations? Pediatrics 1994; 94:281–283. 10. Fowkes FG, Lunn JN, Farrow SC, et al. Epidemiology in anaesthesia. III: mortality risk in patients with coexisting physical disease. Br J Anaesth 198;54:819–825.

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3 The Biologic Effects of Low-Level Radiation Martin Charron

Few topics engender more vigorous debate than the biologic effects of low-level radiation and selection of a mathematical model to predict the incidence of cancer. A recent review on radiation risk stated (1): The A-bomb survivors represent the best source of data for risk estimates of radiation-induced cancer. It is clear that children are ten times more sensitive than adults to the induction of cancer. There are no assumptions, and no extrapolation indicated.

This chapter provides data that suggest that exactly the opposite of the above three statements applies; that is, I present a large amount of data indicating the linear no-threshold theory is erroneous. To that effect, this chapter discusses a review article (2) that scrutinized numerous scientific studies that arrived at drastically different conclusions. I present the information in four sections: the available experimental data, studies looking at the biologic effects of background radiation, the experimental evidence obtained from medical exposure to radiation, and in vitro studies. First, let’s look at the experimental data available on radiation risk. The only study that suggested a higher risk of cancer with low levels of radiation is the retrospective study by Ron and Modan (3) of 11,000 children treated for tinea capitis. The incidence of thyroid cancer was higher, especially in children less than 5 years old. Because the study was retrospective, the dose range was estimated to be 4.5 to 50 rem. But there are limitations of retrospective studies, as well as significant inaccuracies encountered in estimating radiation exposure. Also, a large proportion of the children received a dose (calculated to be) greater than 10 Rem. Therefore, it seems very inappropriate to draw any conclusion from this study, which was of dubious quality at best. All the other studies, of much higher quality, done on the same topic have led to the opposite conclusions. A study of 14,624 infants less than 30

M. Charron

16 months of age treated for hemangioma did not reveal a higher incidence of cancer (4). Similarly, a Finland study of 1 million children, after the Chernobyl accident, did not reveal a higher incidence of cancer (5). Hjalmars et al. (6) reported no change in cancer incidence in a study of 1.6 million children in Sweden. The study by Rallison et al. (7), looking at the radiation fallout in Utah, reported similar results. Finally, a study of 35,074 patients who received diagnostic doses of iodine radioisotope 131I did not find a higher incidence of cancer (8). Based on those studies of millions of children, it seems appropriate to conclude that low-level radiation does not increase the incidence of cancer, even in children. We now review the conclusions stemming from studies about the biologic effects of background radiation. A Chinese study of 73,000 persons, comparing radiation doses of 96 mrem/yr versus 231 mrem/yr, found no difference in the incidence of cancer. Similarly, the study by Amsel et al. (9) comparing the incidence of cancer in a population of 825,000 patients living at an altitude of 1000 feet to the incidence in a population of 350,000 persons living at 3000 feet did not find a difference in the incidence of cancer between the two populations. One study comparing four groups living at different altitudes actually disclosed a negative dose-risk correlation (10). In the United States, a study looking at the radiation exposure of 1730 counties also found a negative dose-risk correlation (11). One more study of indoor radon exposure did not find any positive correlation (12). As for the experimental evidence from medical exposure to radiation, a study by Saenger et al. (13) evaluated 33,888 Graves’ disease patients treated with either surgery or with 131I. The data revealed fewer complications in patient treated with 131I. A study in 10,552 patients (8) and another study of 46,000 diagnostic doses of 131I (14) did not disclose any higher incidence of cancer. Looking at occupational exposure, data collected in approximately 200,000 persons (15–17) did not reveal an increase in cancer, notwithstanding that in one of those studies the mortality rate from cancer was lower in patients who were radiated! Also, the International Association for Research on Cancer study of 95,673 monitored radiation workers in the United States, the United Kingdom, and Canada found 3830 deaths for all cancers except leukemia but no deaths exceeding what was expected (18). No support for the linear nothreshold theory can be found here either. Finally, several studies have reported that workers who inhaled plutonium have lower lung cancer mortality rates than those not thus exposed (19–21). Contrary to impressions generated by the media, no record exists of cancer deaths resulting from human exposure to plutonium. Probably the most significant data on low-level radiation exposure in humans is still in the research stage, but preliminary results are interesting (22). In Taipei and other areas of Taiwan, 1700 apartment units were built using steel contaminated with cobalt 60, exposing 10,000 occupants for 16 years to an average, according to preliminary estimates, of 4.8 rem in the first year and 33 rem in total (23). From national

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Taiwan statistics, 173 cancers and 4.5 leukemias would be expected from natural sources, and according to the linear no-threshold theory, there should have been 30 additional leukemias. However, a total of only five cancers and one leukemia have occurred among this group (23). There are no statistically sound, well-designed studies that have validated the applicability of the linear no-threshold model at low doses (2). On the contrary, there is a suggestion that low-level exposure may be beneficial. This has been dubbed hormesis, and there are myriad of studies that suggest the beneficial effects of radiation. A study in human lymphocytes showed a protective effect of exposure from low-dose 3H to subsequent exposure to 150 rem of x-rays (24). Shadley and Dai (25) found that preexposure of human lymphocytes to 5 rem reduces the number of DNA aberrations induced by 400 rem. Sanderson and Morely (26) found a decrease in mutagenesis. Kelsey et al. (27) found fewer mutations from 300 rem if human lymphocytes are preexposed to 1 rem of radiation. Shadley and Wolff (28) found a decrease in the number of DNA breaks if cells are irradiated with less than 20 rem. Fritz-Niggli and Schaeppi-Buechi (29) found lower embryonic mortality when Drosophila melanogaster eggs are exposed to 200 rem. Finally, ingenious experimental techniques have been developed for observing the effects of a single alpha particle hitting a single cell. Miller et al. (30) found that the probability for transformation to malignancy from N particle hits on a cell is much greater than N times the probability for transformation to malignancy from a single hit. This is a direct violation of the linear no-threshold theory, indicating that the estimated effects based on extrapolating the risk from high exposure, represented by N hits, greatly exaggerate the risk from low-level exposure as represented by a single hit. The aforementioned data indicate that the linear nonthreshold model is unable to predict the biologic effects of low-level radiation, and consequently grossly overestimates the incidence of those effects. We shall demonstrate that this viewpoint that has exaggerated the risk from low-level exposure unduly poses a burden that is detrimental to the general welfare. After a review of studies on natural, occupational, and medical exposure to radiation, health risk from low-level dose could not be detected above the “noise” of adverse events of everyday life (2). No available data confirm the hypothesis that children are more radiosensitive than adults (2). The evidence is consistent with the statement from the Health Physics Society that the health risk from the exposure to up to 10 rem is “either too small to be observed or nonexistent” (31). A sentiment has recently developed in the community of radiation health scientists to regard the risk estimates in the low-dose region that are based on the linear no-threshold theory as being grossly exaggerated or completely negligible (22). The data regarding leukemia among atomic bomb survivors (32) strongly suggest a threshold greater than 20 centisievert (cSv) (22). The evidence presented in that review leads to the conclusion that the linear nonthreshold theory fails badly in the

M. Charron

low-dose region because it grossly overestimates the risk from lowlevel radiation (22). A controversial analysis and interpretation by Pierce et al. (32) of some of the A bomb survivor data from Japan suggested that a linear model is valid at exposures as low as 50 millisievert (mSv) and that this is the lowest dose linked to a statistically significant radiogenic risk. In other independent analyses of the same data, a curvilinear doseresponse also provided a satisfactory fit to the Japanese data (33). Heindenreich et al. (34), using the same data and applying different analytical methods, did not find any evidence for increased tumor rates below 200 mSv. Finally, if error bars are ignored (22), the points suggest a linear relationship with the intercept at a near-zero dose. The data themselves give no statistically significant indication of increased incidence of cancer for doses of less than 25 cSv. In fact, considering only the three lowest dose points, the slope of the dose-response curve has a 20% probability of being negative (risk decreases with increasing dose) (22). The data largely comes from observation at relatively high doses and dose rate and do not suffice to define the shape of the dose-response curve in the millisievert dose range; however, it is noteworthy that “the dose-response curve for the overall frequency of solid cancers in the atomic-bomb survivors is not inconsistent with a linear function” (35). It is important to note that the rate of cancer in most populations exposed to low-level radiation has not been found to be detectably increased, and that in most cases the rate has appeared to decrease (35). The same report asserts that low-dose epidemiologic studies are of limited value in assessing dose-response relationship and have produced results with sufficiently wide confidence limits to be consistent with an increased effect, a decreased effect, or no effect. For some types of tumors there is actually a decrease in cancer frequency with exposure to radiation (35). Finally, let us consider a legal interpretation in this country of the current scientific data. Recently, a U.S. federal court dismissed all 2100 lawsuits against GPU Nuclear Corporation that claimed radiation injury from the 1979 Three Mile Island accident because of lack of evidence that anyone had received doses greater than 100 mGy (36). The court determined that there is consensus within the scientific community that “at doses below 10 rems [100 mGy], the casual link between radiation exposure and cancer induction is entirely speculative.” The Health Physics Society recommends against quantitative risk assessment of radiogenic health effects below an individual dose of 50 mGy in 1 year (36). The former vice chancellor of Oxford University (37) stated that risk perception is intricate, as it involves fear and dread. However, an oversimplified algorithm is likely to prevent useful empirical application of radiation for the health benefit of children. In addition to the large number of studies we have reviewed, numerous scientific groups believe the linear no threshold model grossly overestimates the incidence of biologic effects, if any, of low-level radiation (38–49).

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References 1. Hall EJ. Lessons we have learned from our children: cancer risks from diagnostic radiology. Pediatr Radiol 2002;32:700–706. 2. Ernst M, Freed ME, Zametkin AJ. Health hazards of radiation exposure in the context of brain imaging research: special consideration for children. J Nucl Med 1998;39(4):689–698. 3. Ron E, Modan B. Benign and malignant thyroid neoplasms after childhood irradiation for tinea capitis. J Natl Cancer Inst 1980;65:7–11. 4. Lundell M, Holm L. Mortality from leukaemia after irradiation in infancy for skin haemangioma. Radiat Res 1996;145:595–601. 5. Auvinen A, Hakama M, Arvela H, et al. Fallout from Chernobyl and incidence of childhood leukaemia in Finland. Br Med J 1994;309:151–154. 6. Hjalmars U, Kuldorf M, Gustaffson G, on behalf of the Swedish Child Leukaemia Group. Risk of acute childhood leukaemia in Sweden after the Chernobyl reactor accident. Br Med J 1994;309:154–157. 7. Rallison M, Dobyns B, Keating R, et al. Thyroid nodularity in children. JAMA 1975;233:1069–1072. 8. Holm L, Wilklund K, Lundell G, et al. Thyroid cancer after diagnostic doses of 131I: a retrospective cohort study. J Natl Cancer Inst 1988;80:1132–1138. 9. Amsel J, Waterbor J, Oler J, Rosenwaike I, Marshall K. Relationship of sitespecific cancer mortality rates to altitude. Carcinogenesis 1982;3:461–465. 10. Frigerio NA, Stowe RS. Carcinogenic and genetic hazard from background radiation. In: Biological and Environmental Effects of Low-Level Radiation. Vienna: International Atomic Energy Agency, 1976. 11. Cohen B, Colditz G. Tests of the linear no-threshold theory for lung cancer induced by exposure to radon. Environ Res 1994;64:65–69. 12. Blot W, Xu Z, Boice J, et al. Indoor radon and lung cancer in China. J Natl Cancer Inst 1990;82:1025–1030. 13. Saenger E, Thoma G, Tompkins E. Incidence of leukaemia following treatment of hyperthyroidism. JAMA 1968;205:855–862. 14. Hall P, Boice J, Berg G, et al. Leukaemia incidence after 131I exposure. J Natl Cancer Inst 1992;340:1–4 15. Kendall G, Muirhead C, MacGibbon B, et al. First analysis of the national registry for radiation workers: occupation exposure to ionizing radiation and mortality. Br Med J 1992;304:220–225. 16. Doody M, Mandel J, Boice JJ. Employment practices and breast cancer among radiologic technologists. J Occup Environ Med 1995;37:321–327. 17. Gilbert ES, Fry SA, Wiggs LD, Voelz GL, Cragle DL, Petersen GS. Analyses of combined mortality data on workers at the Hanford Site, Oak Ridge National Laboratory, and Rocky Flats Nuclear Weapons Plant. Radiat Res 1989;120:19–35. 18. Cardis E, Gilbert ES, Carpenter L, et al. Effects of low doses and low dose rates of external ionizing radiation: cancer mortality among nuclear industry workers in three countries. Radiat Res 1995;142:117–132. 19. Tokarskaya ZB, Okladlnikova ND, Belyaeva ZD, Drozhko EG. Multifactorial analysis of lung cancer dose-response relationships for workers at the Mayak Nuclear Enterprise. Health Phys 1997;73:899–905. 20. Voelz GL, Wilkinson CS, Acquavelle JF. An update of epidemiologic studies of plutonium workers. Health Phys 1983;44(suppl 1):493–503. 21. Gilbert ES, Petersen GR, Buchanan JA. Mortality of workers at the Hanford site: 1945–1981. Health Phys 1989;56:11–25. 22. Cohen BL. Review cancer risk from low-level radiation. AJR 2002;179: 1137–1143.

M. Charron 23. Luan Y. The effects of low and very low doses of radiation on human health. Trans Am Nucl Soc 1999;18–23. 24. Olivieri G, Bodycote J, Wolff S. Adaptive response of human lymphocytes to low concentrations of radioactive thymidine. Science 1984;223:594–597. 25. Shadley J, Dai G. Cytogenic and survival adaptive responses in G-1 phase human lymphocytes. Mutat Res 1992;265:273–281. 26. Sanderson B, Morely A. Exposure of human lymphocytes to ionizing radiation reduces mutagenesis by subsequent ionizing radiation. Mutat Res 1986;164:347–351. 27. Kelsey K, Memisoglu A, Frenkel D, Liber H. Human lymphocytes exposed to low doses of x-rays are less susceptible to radiation-induces mutagenesis. Mutat Res 1991;263:197–201. 28. Shadley J, Wolff S. Very low doses of x-rays can cause human lymphocytes to become less susceptible to ionizing radiation. Mutagenesis 1987;2:95– 96. 29. Fritz-Niggli H, Schaeppi-Buechi C. Adaptive response to dominant lethality of mature (class A) and immature (class B) oocytes of D. melanogaster to low doses of ionizing radiation: effects in repair-proficient (yw) and repair-deficient strains (mei 41D5 and mus 320DI). Int J Radiat Biol 1991;59: 175–184. 30. Miller RC, Randers-Pehrson G, Geard CR, Hall EJ, Brenner DJ. The oncogenic transforming potential of the passage of single alpha particles thought mammalian cell nuclei. Proc Natl Acad Sci USA 1999;96:19–22. 31. Health Physics Society. Radiation risk in perspective: position statement of the Health Physics Society (adopted January 1996). In: Health Physics Society Directory and Handbook. 1998–1999. McLean, VA: Health Physics Society, 1998:238. 32. Pierce DA, Shimizu Y, Preston DL, Vaeth M, Mabuchi K. Studies of the mortality of atomic bomb survivors, report 12.1 Cancer: 1950–1990. Radiat Res 1996;146:1–27. 33. Little MP, Muirhead CR. Evidence for curvilinearity in the cancer incidence dose-response in the Japanese atomic bomb survivors. Int J Radiat Biol 1996;70(1):83–94. 34. Heindenreich WF, Jacob P, Paretzke HG. Exact solutions of the clonal expansion model and their application to the incidence of solid tumors of atomic bomb survivors. Radiat Environ Biophys 1997;36(1):45–58. 35. NCR Report No. 136. Evaluation of the linear-nonthreshold dose-response model for iodizing radiation. Recommendation of the National Counsel on Radiation Protection and Measurements. Society of Nuclear Medicine, June 4, 2001, pp. 279–286. 36. Mossman KL. The linear no-threshold debate: where do we go from here? Med Phys 1998;25(3):279–284. 37. Southwood TRE. Crookshank Lecture, risk from radiation—perception and reality. Clin Radiol 1994;49:1–6. 38. Stewart A. A-bomb data: detection of bias in the Life Span Study cohort. Environ Health Perspect 1997;105(6):1519–1521. 39. Kellerer AM, Nekolla E. Neutron versus gamma-ray risk estimates. Inferences from the cancer incidence and mortality data in Hiroshima. Radiat Environ Biophys 1997;36(2):73–83. 40. Heidenreich WF, Luebeck EG, Hazelton WD, Paretzke HG, Moolgavkar SH. Multistage models and the incidence of cancer in the cohort of atomic bomb survivors. Radiat Res 2002;158(5):607–614. 41. Pierce DA, Mendelsohn ML. A model for radiation-related cancer suggested by atomic bomb survivor data. Radiat Res 1999;152(6):642–654.

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Chapter 3 The Biologic Effects of Low-Level Radiation 42. Kellerer AM. The effects of neutrons in Hiroshima. Implications for the risk estimates. C R Acad Sci III 1999;322(2–3):229–237. 43. Little MP, Muirhead CR. Curvature in the cancer mortality dose response in Japanese atomic bomb survivors: absence of evidence of threshold. Int J Radiat Biol 1998;74(4):471–480. 44. Hoel DG, Li P. Threshold models in radiation carcinogenesis. Health Phys 1998;75(3):241–250. 45. Sinclair WK. The linear no-threshold response: why not linearity? Med Phys 1998;25(3):285–290. 46. Stewart A. A-bomb data: detection of bias in the Life Span Study cohort. Environ Health Perspect 1997;105(suppl 6):1519–1521. 47. Kellerer AM. Radiation risk-historical perspective and current issues. J Radiol Prot 2002;22(3A):A1–10. 48. Ron E. Ionizing radiation and cancer risk: evidence from epidemiology. Radiat Res 1998;150(5 suppl):S30–41. 49. Heidenreich WF, Paretzke HG, Jacob P. No evidence for increased tumor rates below 200 mSv in the atomic bomb survivors data. Radiat Environ Biophys 1997;36(3):205–207.

4 Dosage of Radiopharmaceuticals and Internal Dosimetry Xiaowei Zhu

Dosage of Radiopharmaceuticals Radiopharmaceuticals are widely used for diagnostic imaging and radiation therapy. Although radiation therapy uses damage to living tissue to the advantage of the patient, this damage, however, is a limitation for the diagnostic application. Radiation dosages for specific indications are optimized based on thorough studies performed on animals and through clinical trials on human subjects prior to approval for clinical applications. Proper dosages are derived through careful study of pharmacokinetics, the physical characteristics of the radionuclide, metabolism of the subject, and the pharmacodynamics of the radiopharmaceutical in animal and human subjects. The chemical- and radiotoxicities and adverse reactions are well understood before an optimal and safe dosage is recommended. Doses are typically scaled by weight, or total body surface area, and reduced for children. The recommended dosage for a specific indication and route of administration are stated by the drug manufacturers in the package insert, and are readily available online.

Internal Radiation Dosimetry To assess the effects of radiation on a living organ, it is important to understand and quantify radiation energy deposited and absorbed by that organ. This deposition/absorption of energy is called radiation absorbed dose. Internal radiation dosimetry involves the studying of energy absorbed by the organs from an internally deposited radionuclide. It includes the study of physical characteristics of radionuclides, pharmacokinetics and biokinetics of the radiopharmaceutical, as well as establishing assumptions and models for calculating absorbed radiation energy. Radiation Absorbed Dose Radiation absorbed dose is defined as the quantity of radiation energy absorbed by a unit mass of absorber material (e.g., bone 37

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marrow, body tissue, etc.). The SI unit for radiation absorbed dose is the gray (Gy). 1 Gy = 1 joule energy absorbed/kg of absorber medium However, the traditional unit rad, is used more commonly in the United States. 1 rad = 100 erg energy absorbed/g of absorber medium 1 rad = 0.01 Gy Radiation absorbed dose is proportional to several key estimated components. These components include (1) the amount of radioactivity in the source organ, (2) the residence time of radioactivity in the source organ, (3) the type and amount of radiation energy emitted by the radioactivity in the source organ, and (4) the fraction of the emitting energy from the source that is absorbed by the target organ. The fraction is dependent on the geometric and anatomic relationship of the source to target organs. To calculate the radiation absorbed dose, we need to quantify each component discussed above. Quantifying each component that contributes to the radiation absorbed dose can be difficult due to the complex nature of metabolic systems and to differences in patient anatomy. Therefore, the calculation of radiation absorbed dose is really an estimate of quantity based on standard anatomic and kinetic models and reasonable assumptions. Absorbed Dose Cumulated Radioactivity à The radiation dose delivered from a source organ to a target organ is dependent on the amount of radioactivity in the source organ and the length of time the radioactivity resides in the source organ. Due to the continuous uptake and elimination of the radiopharmaceutical administered to the living system, and physical decay of the radionuclide, the radioactivity in each organ is a function of time. Mathematically, the cumulated radioactivity, Ã, can be expressed as

˜ = • A(t)dt A Ú 0

(1)

where A(t) is the radioactivity in source organ at the time of t (Fig. 4.1). à accounts for the radioactivity in the organ, and how long it resided in source organ (component 1 and 2 discussed above). The units for à are mCi-hr. A(t) is different from organ to organ, and varies in individual living systems. However, it can be estimated from studying the pharmacokinetics of the radiopharmaceutical of the source organ. A timeradioactivity curve can be established for each source organ by following the uptake and excretion of the radionuclide in the organ. A(t) is a function of the physical and biologic decay of the radiophar-

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Activities in Source Organ

Cumulated Radioactivity

~ Area = A = • A(t)dt 0

Time

Figure 4.1. Time-activity curve. The area under is the curve is Ã, the accumulated radioactivity in the source organ.

maceutical. A simplified mathematical model of instantaneous and exponential elimination of the radiopharmaceutical in the source organ can be described as A(t) = A0e-let

(2)

le = lp + lb

(3)

and

where le is the effective decay constant, and lp and lb are the physical and biologic decay constants, respectively. If the half-life is known, the decay constant can be calculated as l=

0.693 . T1 2

(4)

Therefore, equation 1 becomes ˜ = A0 = 1.44Te A0 A le

(5)

where Te is the effective half-life. Equilibrium Absorbed Dose Constant, D The amount of radiation energy emitted per unit of accumulated radioactivity in the source organ can be calculated if the type, energy,

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and frequency of each emission of the radionuclide are known. If we designate Ei as the energy of the ith emission, ni is the frequency of that emission. The amount of radiation energy emitted per unit of accumulated radioactivity can then be described as Di = 2.13niEi

(6)

where Ei is in MeV and Di is in (g-rad/mCi-hr). Di is defined as equilibrium absorbed dose constant of the ith emitter. The energy emitted from the ith emission of the radionuclide in the source organ is a product of the equilibrium absorbed dose constant, Di, and accumulated radioactivity, Ã. If a radionuclide deposited in the source organ has more than one emission, the equilibrium absorbed dose constant should be calculated for each emission and summated. Total Energy Absorbed by Target Organ, D Due to the distance and attenuation between the source organ and target oranges, only a fraction of the energy emitted by the source organ is absorbed by the target organ. This fraction factor needs to be quantified so that the total absorbed dose by the target organ can be estimated. Absorbed Fraction f The absorbed fraction depends on the geometric relationship of the source and target organ, the emission energy of the radionuclide, and the composition of the source organs, the target organ, and those organs in between. Mathematically, the absorbed fraction of the ith emission of the radionuclide can be expressed as fi(tk ¨ sj). The energy absorbed by the target organ, tk, from the ith emission of the radionuclide in source organ, sj, is equal to Ãjfi(tk ¨ sj)Di. So the total energy absorbed by target organ, tk, from all emissions in the source organ, sj, is ˜ j f i (tk ¨ s j )D i . Energy Absorbed (g - rad) = A Â

(7)

i

Because the absorbed dose is defined as energy absorbed in unit mass, the dose delivered from the source organ, sj, to the target organ, tk, is ˜jˆ ÊA D(tk ¨ s j )(rad) = Á ˜ Â f i (tk ¨ s j )D i Ë mk ¯ i

(8)

where Ãj is the cumulated activity in source organ, sj, and mk is the mass of the target organ, tk. The total dose to the target organ can be obtained by summing the doses from all the source organ of the body: D(tk )(rad) = Â D(tk ¨ s j ). j

The calculation of absorbed fraction, f, for each penetrating emission, for example, photons, is very complicated, as it is highly dependent on the energy of the radiation emission, the geometry between the target and source organs, and the characteristics of the tissue and organ. The range of f is between 0 and 1 from the source organ to target

X. Zhu

organ (target organ can be the source organ itself) for photons with emitting energy >10 keV. When the target organ is the same as the source organ, and electron or photon energy is 0.999 0.97 0.90 0.17 0.89 0.95 0.23

Emax (MeV) 0.960 1.198 1.732 0.633 0.545 1.673 2.921 3.379 1.535

Production Cyclotron Cyclotron Cyclotron Cyclotron Reactor Cyclotron Daughter of 68Ge Daughter of 82Sr Cyclotron

Source: Data from Chang J. Table of Nuclides, KAERI (Korea Atomic Energy Research Institute). Available at http:// atom.kaeri.re.kr/ ton/ .

t1 2 =

ln 2 l

(3)

as it can be worked out from Equation 2. The half-lives of isotopes of interest in nuclear medicine range from seconds to years. In SPECT, the most widely used isotope, 99mTc, has a half-life of about 6 hours. For PET, the half-life of fluorine 18 (18F) is approximately 2 hours. This is about ideal because this is enough time to allow for isotope production, radiopharmaceutical synthesis, dose delivery, and imaging time while minimizing the dose burden to the patient, which also depends on t1/2. The decay constant l is related to the number N of nuclei present in the sample and the activity by the relationship A = lN.

(4)

It should be noted that Equation 2 governs the rate of decay of nuclei, which is not always the same as the rate of emission of positrons. In fact, different modes of decay may be available to a nucleus. For example, iodine 124 (124I) undergoes b+ decay only in 23% of the cases; in the remaining 77% the decay mode is EC, which does not produce any positrons. In such cases, it is important to account for this branching ratio when estimating the rate of positron emission from the decay rate of the nuclei. If the problem is to predict the decay over time of a certain type of activity measured at some other point in time, Equation 2 can be applied without worrying about the branching ratio, which is already accounted for in the measurement.

Interaction with Matter Positron Annihilation After decay, the positron leaves the site of emission and slows down in the surrounding material. As the positron is a relatively light, charged particle, it undergoes large-angle scattering interactions with other charged particles, which result in a tortuous path. The distance

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Figure 8.2. The small (~0.5-degree) deviation from 180 degrees in the emission of annihilation photons due to the residual momentum of the e- - e+ pair causes the corresponding line of response to be slightly misplaced (by the distance d) from the annihilation site. This error is small, but it does limit the ultimate resolution of PET scanners. Compton scattering results in misplacement of events for the same basic reason, that is, because an angular deviation q is introduced. In this case, misplacement is much more severe because q is usually much greater than 0.5 degrees.

traveled from the nucleus, that is, the range of the particle, depends on the energy E with which the photon is emitted, the density of the surrounding material, as well as on the trajectory followed. The range is longer for positrons emitted with higher E. Maximum and average values of the range are found in the literature. For 18F, carbon 11 (11C), nitrogen 13 (13N), and oxygen 15 (15O) the average range is 0.6, 1.1, 1.5, and 2.5 mm, respectively. During slowdown or once it has come to rest, the positron may combine with a surrounding electron and annihilate, that is, undergo a reaction in which positron and electron disappear and their total energy is converted into two or more photons. Fortunately, the great majority of annihilations results in the simultaneous emission of two (almost) back-to-back photons, each with an energy of 511 keV (4). The distance that each of the two annihilation photons must cover to reach the scanner depends on where the annihilation took place, so that the two photons can reach the scanner at slightly different times. However, this relative delay cannot be larger than a few nanoseconds (billionths of a second). The basic idea of PET is to attribute an event to an LOR every time that two photons are detected in approximate time coincidence. Because the positron travels some distance from the nucleus before annihilation, annihilation photons are not generated at the site of the emitting nucleus, as happens for single photon emitters. Consequently, the nucleus can be located only approximately, the approximation worsening for increasing positron range. A second physical factor that intrinsically limits the spatial resolution of PET scanners is that annihilation photons are not emitted exactly along the same line (i.e., at a relative 180 degrees) in the laboratory frame of reference (5). This means that the annihilation site in general does not lie exactly on the line connecting the detection locations of the two photons (Fig. 8.2).

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The ensuing positioning uncertainty d is proportional to the diameter of the scanner (6) and reaches about 2 mm for a diameter of 90 cm. With current technology, this is one of the main factors limiting the resolution of whole-body PET scanners. Gamma Attenuation, Scattering, and Random Coincidences Annihilation photons may undergo interaction with surrounding materials before detection. Photons in the energy range relevant to PET interact with matter through two principal mechanisms: photoelectric absorption and Compton scattering. In photoelectric absorption, a photon is absorbed in an interaction with an atom in the surrounding material. Effectively, the final result of a photoelectric event is that the photon disappears. Because in PET both annihilation photons need to be detected to form a valid event, photoelectric absorption of either photon outside the detector is sufficient to lose the annihilation event for image formation. Depending on the location and direction of the annihilation, the likelihood of attenuation changes, with higher losses for emission points lying deep within the patient. Therefore, attenuation must be compensated to obtain realistic images and quantitative data. Attenuation correction strategies for PET are described below and are based on the observation that, unlike in SPECT, in a collected event the total photon path crosses the object from side to side (Fig. 8.3). If a point source located anywhere along this line emits N0 photons per unit time along the line, the rate at which events are recorded is C = N0 e-mrD

(5)

where m is the mass attenuation coefficient of the material, which is known from its atomic composition and the energy of the photons, and r is its density. The key point is that the factor e-mrD can be obtained by direct measurement. In fact, if an external source of known activity A0 is placed at one end of a given LOR, the count rate A measured at the other end of the LOR is given by A = A0 e-mrD.

(6)

-mrD

Therefore, the factor e can be obtained experimentally from the ratio A/A0 and then used to divide the coincident count rate C to recover the activity N0. Note that this applies for sources anywhere along the LOR, that is, at any depth in the object.

Figure 8.3. Attenuation correction in PET. The count rate recorded at detector 2 is C when exposed to annihilation photons in coincidence with detector 1 and A when exposed to the source of intensity A0. The line connecting detector 2 to the source is separate from that connecting it to detector 1 only for illustration purposes.

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For 511-keV photons in biologic materials, Compton scattering is much more likely to occur than photoelectric absorption. In Compton scattering, the photon loses some energy and its path is deviated by an angle q (Fig. 8.2). The scattering angle is again selected in a random process governed by quantum mechanical laws (e.g., ref. 7). The energy of the scattered photon is related to q by the Compton equation: Eg

Eg¢ = 1+

Eg (1 - cos q) me c 2

(7) where Eg is the energy of the incident photon, me is the rest mass of the electron, and c is the speed of light. The product mec2 is a physical constant and its value is 511 keV. The Compton equation shows that photons emerge from scattering with an energy that depends on the scattering angle. For example, for q = 0, or forward scattering, which is the limiting case in which the photon is not scattered at all, E¢g = 511 keV; for q = p, which is the case of backscattering, that is, when the photon turns back, E¢g = 170 keV. Unlike attenuation, scattering does not necessarily remove events from image reconstruction. Rather, it usually causes the incorrect association of a significant fraction of events to LORs, through the same basic mechanism of Figure 8.2, but in a much more dramatic way because of the much larger angular deviation involved. It is not at all uncommon that scatter events are assigned to LORs not even passing through the object, which does not happen for true events (i.e., unscattered events coming from the same annihilation) except for the much smaller effect of non-colinearity. Scatter events, in principle, could be rejected by measuring the energy of incoming photons and then accepting only those arriving with the correct energy, that is, 511 keV. As discussed below, existing equipment allows only an approximate measurement of the energy of photons, so that it is necessary to accept events with a measured energy of less than 511 keV to avoid discarding too many true events. Therefore, in practice, only photons whose measured energy is above a certain threshold (set at less than 511 keV) are accepted. This threshold is selected by setting the low-level discriminator (LLD) of the scanner. Because the Compton equation shows that E¢g decreases as q increases, increasing the LLD means confining q closer to zero. From Figure 8.2, it is possible to see that this minimizes the error introduced. Whereas a high LLD setting does minimize the impact of scattering events, it has also other implications, as we shall see, and it cannot, alone, completely solve the problem of scatter contamination of the data; other methods, described below, are needed for full scatter compensation. The scattered photon can undergo further scattering, still governed by the same equations. Such events, as well as those in which both annihilation photons are scattered once, are referred to as multiple scattering. Another type of spurious event, besides scattering events, can also enter the image. If more than one nucleus decays at approximately the same time, and for both events one of the two photons is lost, it is still possible that the two survivors are detected in coincidence. In this case a LOR is mistakenly associated to the unrelated photons (Fig. 8.4). This

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Figure 8.4. Pictorial representation of (A) a true coincidence, (B) a scatter event, and (C) a random coincidence. In B and C, the dashed line represents the line of response to which the event is assigned. It coincides with the path of the photons (solid line) only in case A.

type of event is called a random coincidence. The likelihood of random coincidences depends on the level and spatial distribution of activity and the temporal width of the coincidence window, as well as the geometry of the object. To appreciate this, it is helpful to consider that after the detection of a first photon above the LLD, the scanner waits up to a time t for the photon emitted simultaneously to arrive. The time interval 2t is called the time coincidence window. If the rate at which the first event is recoded is N events per unit time, then the rate at which random coincidences occur in the scanner is tN2. Time coincidence windows are usually set between 6 and 12 ns (billionths of a second, i.e., 10-9 s), depending on the scintillator.

PET Instrumentation It is desirable to detect photons with high spatial, energy, and time resolution, with high sensitivity and count rate capabilities, all at reasonable cost. Different classes of detectors of high-energy photons have long been under development; no single class, however, offers the best performance in all respects. For example, solid-state detectors offer the best energy resolution, but their sensitivity is usually low, especially when their cost and availability over a large area are considered. Commercial clinical PET cameras are based on scintillation detectors. In these systems, the photon interacts with a scintillating material, which converts the photon energy into visible or near-visible light. These low-energy photons are then conveyed to PMTs for conversion into an electrical signal. The front end of the PMT is the photocathode, which is a thin element of material capable of absorbing light photons and emitting electrons (called photoelectrons, because they are released by incident light) in proportion to the number of absorbed photons. Electrons are then multiplied by a cascade of electrodes (dynodes) to generate a measurable current and voltage, which is the output of the PMT. In summary, the role of the PMT is to convert the light emitted in the scintillator into an electric signal that is directly proportional to the intensity of the light signal. A much more compact alternative to PMTs are photodiodes. These are semiconductor devices capable of

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playing the same role. To date, their use has been hampered by their cost and instability with respect to fluctuations of temperature and applied voltage, and, often, the consequent need for cooling. The electric signal generated by the PMT is then sent through pulse processing electronics that collect and process signals from the entire scanner. The part of this processing most typical of PET is the identification of events in time coincidence and their location on the detector for assignment to a LOR. Scanner designs differ mainly in the choice of the scintillator and the way light is conveyed (coupled) to PMTs. Scintillating Material Scintillators commonly considered for PET are listed in Table 8.2 along with some properties that characterize their performance. An ideal scintillator would have high sensitivity, that is, it would detect all incoming photons and record their energy and location of interaction accurately. Moreover, the timing properties of scintillators are also important because with fast scintillators a narrow time coincidence window can be used, which reduces the rate at which random coincidences are acquired as well as dead time effects (see below). High sensitivity can be obtained with large volumes of scintillators. However, it is also important to be able to stop photons in a small volume to obtain precise positioning and thus high-resolution images. The thickness of a material necessary to absorb photons is regulated by the product m* = mr (e.g., see Equation 5). Materials with a high value of m* can stop photons within a relatively small distance and are preferred. As already mentioned, an accurate energy measurement is important to differentiate scattering from true coincidence events. Figure 8.5 is a pictorial representation of the response of a real detector. This figure shows the number of incoming photons as a function of their measured energy. The peaks centered on 511 keV are due to 511-keV photons; because not all of these photons are exactly at 511 keV, it is evident that a real detector does not always measure energy accurately. This is due to a number of factors. An accurate measurement requires that, first, all the energy of the photon be deposited in the detector; second, that all deposited energy be transformed into light and converted into current with minimal fluctuations and losses; and, third, that all the current be collected and analyzed by pulse processing electronics.

Table 8.2. Properties of some scintillators used in PET NaI(Tl) Attenuation coefficient m* (cm-1) Effective Z Light output (photons/keV) Light decay constant (ns)

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Figure 8.5. Energy spectrum for scintillators with good (solid line) and poor energy resolution (En. Res.) (dash). On the left true and scattering events are shown separated but in reality these events are indistinguishable to the detector; only the sum of the two curves is available (right). For a scintillator with good energy resolution it is possible to set the low-level discriminator (LLD) at a higher level to reject scatter with minimal loss of true events.

For the incoming photon to deposit all its energy, it is important that the photon-crystal interaction be a photoelectric rather than a Compton event. Because the likelihood of Compton scattering is proportional to the atomic number Z of the medium, whereas the likelihood of a photoelectric event is proportional to Z5, scintillators with a high Z (or effective Z for compounds) are preferable to maximize the fraction of events with full energy deposition. It is not possible to entirely avoid statistical fluctuations, which are also an inherent part of the detection mechanism. In fact, the number of light photons n produced by a high-energy (gamma) photon is determined in a random process. For this reason, photons having the same energy produce a varying n. Other statistical processes are involved in the conversion of photons to photoelectrons and in the multiplication of electrons inside the PMT. Because the energy of the event is measured by collecting over time (integrating) the PMT current, the final effect is an imperfect energy measurement, distributed approximately along a gaussian curve, which results in the peaks in Figure 8.5. A statistical analysis of the process shows that energy resolution, which gets worse as the gaussian becomes wider, depends mainly on the light yield of the scintillator. Table 8.2 shows the light output of different scintillators. A high light output minimizes relative fluctuations in the current and is associated with good energy resolution. Figure 8.5 also shows the case of two scintillators: one with good and one with poor energy resolution. From inspection of the peaks in the figure, good energy resolution allows a more precise measurement of the energy. Photons that undergo Compton scattering in the patient (and thus have an energy of less than 511 keV) and deposit their full energy in the detector give the contribution shown to the left of the peaks in Figure 8.5. The measured energy of these photons is also blurred by the statistical fluctuations just described. From Figure 8.5 it is clear that scatter and true events cannot be completely separated on the basis of

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their measured energy. However, blurring is less pronounced when energy resolution is good, which allows a relatively better separation of true from scatter events. This observation determines the choice of the LLD of the scanner. From a scatter rejection point of view, the LLD should be as high as possible. However, when the LLD is increased, eventually true events are also discarded. Optimizing the LLD setting, then, involves optimizing a trade-off between maximum sensitivity to true events and minimum sensitivity to scatter events. The advantage of good energy resolution is that it is possible to operate with a higher LLD setting, and thus reject comparatively more scatter, before a significant number of true events is lost. For the same number of true events relatively fewer scatter events are collected, which means that image processing in scanners based on a scintillator with good energy resolution can start from better estimates of the true distribution of the radiotracer. It is important to recognize that other factors also affect energy resolution, such as size of the scintillator, homogeneity of the light output, how the scintillators are coupled to the PMTs, and the successive pulse processing. For example, to maximize energy resolution, a long time should be allowed to collect all the PMT current (integration time). However, this is at odds with the necessity of being able to process separately the next incoming event as soon as possible, that is, to achieve high count rate capabilities, which demand that integration times be kept as short as possible. Because the integration time is mainly driven by the time interval over which light is emitted, the rate at which scintillators emit light is also an important performance parameter. Table 8.2 lists decay times for different scintillators. In this case, a small value indicates a fast scintillator and thus is a desirable property. Energy resolution, then, is related to light output, but it cannot be directly inferred from it. The data in Table 8.2 summarize all the physical parameters important for the evaluation of different scintillators. For example, NaI(T1): sodium iodide [NaI(T1)] has higher light output (and better energy resolution) than bismuth germanate (BGO) and lutetium oxyorthosilicate (LSO), for which sensitivity is much better, with LSO being also significantly faster. BGO has a much higher attenuation coefficient than NaI(Tl), and thus higher sensitivity, but the reduced light output affects negatively its energy resolution. LSO has almost the same attenuation coefficient of BGO, and is much faster than both BGO and NaI. GSO is almost as fast as LSO and in the past has offered better energy resolution at the price of reduced sensitivity. Recent improvements in LSO crystal production have led to energy resolution similar to GSO. Slight variations to the composition of LSO have recently been tested [e.g., lutetium (yttrium) oxyorthosilicate [L(Y)SO], mixed lutetium silicates (MLSs), and lutetium pyrosilicates (LPSs)]. Most of these crystals have properties similar to LSO. It is possible that scanners based on such scintillators will be developed commercially in the near future. Commercial PET scanners based on NaI(Tl), BGO, LSO, and GSO have been deployed on the field. Scanners utilizing barium fluoride (BaF2) and lanthanum bromide (LaBr3) are of particular interest in PET instru-

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mentation research because their fast decay times open the possibility of time-of-flight (ToF) PET. This technique is characterized by low image noise, which compensates for the disadvantage of the relatively low sensitivity of these materials. BaF2 was among the first scintillators considered for ToF PET; more recently, interest has been focusing on LaBr3 because its timing performance is competitive with BaF2 (8) and its superior light output and energy resolution are expected to result in improved spatial resolution and rejection of scatter events. Light Coupling and Spatial Assignment of Events The discussion has so far focused on the efficiency of the detection of one of the two annihilation photons and on the accuracy of the measurement of its energy. Different techniques are used to identify the position at which incoming photons are detected. Apossible approach is to consider them as different compromises between two extreme designs. In the first design, a large, continuous crystal is used and the position of the event is read as in a conventional Anger (gamma) camera. In this design, the light following an interaction is shared by several PMTs facing the crystal (Fig. 8.6A) (9,10). The position of the event is calculated by a weighted average of the coordinates of the center of each PMT, where the weights are determined by the light intensity seen by

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each PMT. This positioning strategy is often called Anger logic, after the name of its developer. For this scheme to work, light needs to spread to several PMTs to allow an accurate calculation of the position. The energy of the event is calculated from the sum of the signals from all PMTs. The same statistical fluctuations that limit energy resolution, then, affect the spatial localization of the event and thus spatial resolution. For this reason, Anger logic designs perform best with scintillators with a high light output. The typical intrinsic resolution of an Anger camera is about 3 mm in SPECT applications but is worse (~5 mm) for PET applications, due to the thicker crystals (25.4 mm NaI vs. 9.3 mm NaI) used to achieve reasonable sensitivity at the energy of the more penetrating 511-keV photons. The major disadvantage of this design is that, following each event, light invades a significant portion of the large crystal and its detection involves several PMTs. Consequently, a large area of the detector is not available for recording other events. This leads to high dead time and decreased maximum count rates. In the second design, the scintillator is cut in an array of very small crystals (pixels), each of which is connected to a single light detector (one-to-one coupling). The advantage of a pixelated design is that the intrinsic spatial resolution of the detector is about half the size of the pixels, which can be cut to a cross section of a few millimeters. A second advantage is that, because pixels are entirely independent, count rate capabilities are much improved. Whereas the continuous crystal design has been implemented in a commercial clinical scanner, one-to-one coupling has been implemented only in small animal and brain research scanners. Its drawbacks are significantly increased cost and complexity because of the large number of small light detectors needed, as well as compromised energy resolution, especially as crystals are made smaller. Hence its application to systems that use fewer pixels and light detectors. Most commercial clinical scanners follow neither of these designs but rather different degrees of compromise between the two extremes. A first architecture, conceptually relatively close to the continuous-crystal design, connects small, independent crystals to a light guide, which is then read out by PMTs in an Anger logic configuration (11) (Fig. 8.6B). The design of the crystals and the light guide carefully limits the number of PMTs involved in the detection of a photon; because scintillation light is not allowed to invade the whole crystal, fewer PMTs are involved and the count rate capability is improved. In the block detector architecture (12), groups of crystals (typically an 8 ¥ 8 cluster) are connected to a 2 ¥ 2 array of PMTs (Fig. 8.6C). The light generated in each crystal is allowed to spread in a controlled manner within the block (this is why crystals are formed by cutting slots of different depths in a block of scintillator) to only four PMTs, which, by use of Anger logic over this very limited area, can identify the crystal in which detection occurs. In yet another design, PMTs assigned to a block are replaced by larger PMTs straddling quadrants of adjacent blocks (quadrant sharing block geometry) (13). An important parameter for comparison is the encoding ratio, which is the average number of crystals per PMT. For a given number of crystals of a given size (i.e., for comparable field of view and resolution),

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independently of the scintillator used, the encoding ratio is inversely proportional to the number of PMTs used. If large PMTs are used, fewer are needed to cover all crystals and the encoding ratio is large. This reduces cost; however, large PMTs also result in reduced count rate capability, because each PMT must serve a large area. Large PMTs are typically used with the continuous light guide and the continuous or pixelated crystal geometry discussed above, which have the advantage of uniform light collection over large areas. This uniformity benefits the energy resolution of the scanner. The best energy resolution is obtained in conjunction with scintillators with high light output. At the other end of the spectrum, scintillators with a low light output are best used with smaller PMTs in a block detector geometry. This has the advantage of more independent modules, which benefits the count rate, but energy resolution is sacrificed with cost and system complexity, which increase because of the larger number of PMTs needed. Depth of Interaction To locate accurately the annihilation photons, the scintillator in an ideal scanner would be infinitely dense and thin. To achieve workable sensitivity, real scanners must use scintillators with thickness on the order of 20 to 30 mm, which are not negligible values. Reconstruction algorithms, however, assume that photon detection takes place at the crystal surface. Figure 8.7 illustrates how this results in a degradation of spatial resolution far from the center of the scanner. The degradation increases with the thickness of the crystals as well as with the distance from the center of the scanner, where it vanishes. At 10 cm from the center, it is typically a few tenths of a millimeter. Depth of interaction, thus, is not likely to play a major role in general and especially in pediatric PET for younger patients, who are imaged only at the center of the scanner. Several schemes have been proposed to mitigate the

Figure 8.7. Pictorial representation of event misplacement due to depth of interaction. Due to penetration, photons can be detected well inside the crystals, but, because no information on the depth of interaction is available, reconstruction algorithms assume that detection takes place at the inside surface of the crystal. At the center of the scanner this has no consequences; however, depending on the radial position r and the length of the crystals, depth of interaction can result in the assignment of the event to an incorrect line of response (LOR) (i.e., to the dashed rather than the solid line).

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problem [e.g. (14,15)], but to date none has yet been implemented in a commercial system. Data Acquisition, Correction, and Image Reconstruction When coincident photons are detected, the event is assigned to the LOR corresponding to the two detection locations and stored. The number of events detected in each LOR is the basic output of the scanner. These raw data are the starting point of image reconstruction. The scanner also acquires other data for the various corrections necessary, for example, for random events, scattering, and attenuation. Detected events whose energy is above the energy threshold (the LLD) are often called single events. If a second single event is detected inside the time coincidence window, a prompt coincidence is obtained. This is not necessarily a true event because photons may have undergone scattering or may have originated from different nuclei (“random” event). Ideally, only true events should be used for reconstruction, but all three kinds are inevitably present in the acquired data, in varying proportions depending on the activity present in the field of view of the scanner, its distribution, and that of the scattering material, along with acquisition parameters such as the time coincidence window and the LLD setting, and the geometry of the scanner, which can be designed for 2D or fully 3D imaging. The simplest PET scanner is composed of a single ring of detectors and thus is capable of acquiring data only in a single transverse plane, that of the ring. Extension to 3D imaging can follow different avenues. The most straightforward is to stack rings of detectors axially and, at the same time, to use tungsten septa to narrow the angle of acceptance of each ring to admit only events originating in the plane of that ring and of a few adjacent rings. In this design, rings operate independently (2D geometry). An alternative is to allow all rings to see the entire object, in which case a fully 3D geometry is realized. Purely transverse data are sufficient for reconstruction of a 3D volume by stacking 2D transverse images, each generated independently from a 2D reconstruction of 2D data. The advantage of 3D geometry is its higher sensitivity. The elimination of the septa, however, increases the sensitivity to true as well as to random and scatter coincidences, for which the increase can be higher than for true events. Three-dimensional geometry affects scanners based on different scintillators to different degrees. In general, it places a premium on scintillators with good energy resolution (which can use a higher LLD and therefore are relatively less sensitive to scatter events) and fast timing (which are relatively less sensitive to random events and can better handle the increased count rate). It is mainly because of scatter that, in practice, in spite of the development of specific correction methods, 3D scanners based on crystals with relatively low energy resolution have not yet achieved performance consistently superior to 2D scanners, with effects measurable in terms of contrast recovery and detectability (16). This fact increases the emphasis on the scatter and random coincidence compensation methods described below.

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As compared to SPECT, PET data lend themselves to correction for physical effects such as attenuation and scatter rather naturally, paving the way for quantitative imaging, that is, for the evaluation of the activity per unit volume present in the object. To reach this goal, considerable effort has been spent in the development of accurate correction methods. Normalization Reconstruction algorithms usually rely on the assumption of an ideal scanner, that is, one for which all parts of the detector ring are uniformly sensitive to incoming photons. In real scanners, a number of factors deviate from this assumption. Normalization is a procedure that corrects the raw data to restore the conditions of an ideal scanner with uniform sensitivity prior to reconstruction. Normalization techniques can be based on the acquisition of data on the scanner, on mathematical models, or on a combination of these two methods (17–21). Regardless of the technique used, normalization data do not need to be acquired for every study. However, because some factors, especially the calibration of the electronics, may drift over time, normalization should be part of quality control procedures and carried out periodically. Attenuation Correction As previously discussed, accurate attenuation correction can be achieved from knowledge of the attenuation exponentials e-mrD for every LOR (22–24). In the simplest methods, these are determined from the emission image by assuming that all regions containing activity have uniform attenuation. Attenuation exponentials are then determined automatically for each LOR by calculating the length of its intersection with these regions. These approaches work well for rather homogeneous parts of the body, such as in brain scans, and have the advantage of introducing no noise into image reconstruction. However, they rely on the assumption of uniform attenuation and so they are much less accurate for irregular distributions of the scatter medium, as in the chest, where the lungs present an attenuation coefficient significantly different from adjacent regions. In these situations, attenuation is better measured with a transmission scan, in which the patient is exposed to an external source of photons. In dedicated PET scanners, line sources of either germanium 68/gallium 68 (68Ge/68Ga) (511 keV) or cesium 137 (137Cs) (662 keV) (25–27) have been used. In PET-CT scanners, it is possible to take advantage of the superior resolution and accuracy of CT data for attenuation correction. However, care must be taken in rescaling the attenuation data from the energy of the measurement (about 60 keV) to 511 keV and in considering the effects of contrast agents, if used. Another potential concern is the incorrect spatial alignment (registration) of the data, which are now effectively acquired on two different scanners, and the consistency of PET with CT data, in which the effects of the patient’s breathing may be different due to the much shorter duration of the scan.

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The effect of attenuation correction is usually obvious in PET images: corrected studies restore activity in the inner parts of the body to its correct, higher level. Because photons are attenuated more when more material is present, the magnitude of the correction is directly related to the size of the patient. Random Events Subtraction Different correction methods for random events are available. Some involve processing of the acquired data, but the most accurate approach requires that additional data with a delayed timing window also be acquired. A delayed timing window is one accepting events coming within a time t after a time (the delay) much larger than t has elapsed since the detection of the first event. These are the so-called delayed coincidences. In true and scatter events, the two photons identifying the LOR originate from the same nuclear decay and thus arrive at the scanner separated by a time shorter than t. Therefore, these events are excluded from the delayed coincidences. On the other hand, random coincidences involve the decay of two different, unrelated nuclei, which happen to produce annihilation photons at the same time by chance. The method of the delayed coincidences assumes that this chance is the same as the chance of producing the photons with a time difference equal to the delay. In summary, delayed coincidences contain only random events that, although not the very same that are part of the image, are still an excellent estimate that can be subsequently subtracted from the data collected with no delay, that is, the actual scan. Whereas subtraction of noisy data from noisy data increases image noise, averaging techniques [also known as variance reduction techniques (28,29)] have been developed to minimize this problem. The number of collected random events is proportional to the time coincidence window t and the square of the singles count rate. Thus, their impact is less relevant in scanners based on a fast scintillator (for which t can be set to a small value) and when low activity is present in the field of view. Because this is usually the case in pediatric PET, especially for younger patients, it is expected that the magnitude of the correction for random events will be smaller than for adults. Scatter Correction Accurate scattering correction is vital for accurate quantification, especially in fully 3D scanners, where the open geometry increases sensitivity to scatter events more than to true events. In theory, because the energy of each incoming photon is available after its detection, scatter could be rejected by simply discarding all detected photons whose energy is not the 511 keV expected for an unscattered photon. In practice, because detectors do not have perfect energy resolution, scattered photons may appear as true events and vice versa. As previously discussed, a careful choice of the LLD minimizes the number of scatter events collected without unduly sacrificing sensitivity to true events. However, some scatter events are still accepted, and for a complete correction additional data processing is necessary.

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Different approaches to the problem have been proposed and have evolved over the years (30–37). Most take advantage of the fact that the scatter distribution is very smooth, that is, even though it can be markedly asymmetric, it varies slowly across the field of view, and it is not very sensitive to sudden variations in the object. Recently, the steady increase in affordable computational capacity has made practical techniques that estimate the spatial distribution of scatter directly from physical principles. These are single scatter simulation (SSS) and Monte Carlo (MC) algorithms (38–40). The calculation starts from the estimate of the distribution of the activity provided by the uncorrected image and the estimate of the scattering medium provided by the attenuation scan. Application of physical laws such as Equation 7 generates an estimate of the scatter distribution, which is then subtracted from the uncorrected image to generate a more accurate estimate of the activity distribution. This estimate is still incorrect because it is still based on the uncorrected image. However, the procedure can be repeated to improve accuracy, until further repetitions do not produce significant corrections. Such techniques have the advantage of being patientspecific and equally applicable to uniform (e.g., brain) and nonuniform (e.g., chest) regions. Single scatter simulation explicitly estimates only single scatter and incorporates the effects of multiple scatter only indirectly; MC techniques can be applied to model accurately both single and multiple scatter (41–43), which can be as much as single scatter in large patients. However, at present, MC methods still need more computational resources than routinely available and in most cases do not seem to provide significant advantages over SSS. Therefore, most clinical systems use different implementations of SSS, which has proven to provide very good estimates, except perhaps for the very heaviest patients, and superior performance than previous correction techniques (40). Because the effect of scatter is to add a rather smooth, featureless background, the effects of scatter on the image are not as evident as those of attenuation. Nevertheless, scatter correction can have a quite dramatic impact on the extraction of quantitative data, especially from cold regions, that scatter tends to “fill in.” In this case scatter correction algorithms should restore the correct, lower intensity. As for attenuation, the relative impact of scatter on image quality is directly related to the size of the patient, large patients being more affected. For this reason, the magnitude of the scatter correction is less relevant for smaller and lighter patients. Furthermore, in this population the large majority of scatter is single scatter, for an accurate estimate of which relatively simple methods such SSS are already routinely available. Dead Time and Decay Correction Dead time is the amount of time during data acquisition in which the scanner is not available for processing new incoming events because it is busy processing previous ones. Data are usually acquired over a given length of time (real time); in the presence of dead time the scanner will be available only for a fraction of the real time (called the

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live time), and, accordingly, the recorded number of events is smaller than that which would be recorded in the absence of dead time. Correction for dead time involves multiplying the acquired data by a factor that will restore this number. Dead time increases with the count rate in the scanner. In general, correction is necessary when data acquired at different count rates need to be compared in some way. This is the case in whole-body studies, where images are formed by juxtaposing images of adjacent sections of the body, each containing a different activity (and thus affected by different dead time); in dynamic studies, because decay and redistribution of the radiotracer cause the count rate to change; and in the evaluation of quantitative measures, such as standard uptake values (SUVs), in which the number of counts is important in an absolute, not only in a relative, sense. At low count rates, events arrive sparsely in time and it is unlikely that an event will be lost because others have just been detected, so the dead time correction is small and may not be necessary. This is the case in many pediatric studies, in which the injected dose is typically low. However, dead time correction does not present any particular disadvantages and is usually always enabled. It is often also necessary to correct the data for the radioactive decay of the isotope. This is obtained by keeping record of the time t elapsed between some reference time (e.g., injection) and each study, and then by multiplying the acquired data by the decay factor elt. This multiplication restores the activity of each data set to that which would have been recorded at the reference time, thus making the data comparable to those acquired at a different time. Figure 8.8 compares the same coronal slice of the clinical study in Figure 8.9B before and after correction for attenuation, scatter, and

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random events. Other than the obvious artifact in slices containing the bladder, which is due to the attempt at reconstructing inconsistent data, relevant features are that before correction contrast in the lungs vs. surrounding tissue is inverted; that the sides of the body appear to have increased uptake; that the liver has not uniform uptake; and that the contrast at the site of the lesion (in the uterus) is also different from that in the corrected image.

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Image Reconstruction Algorithms A complete discussion of image reconstruction algorithms is clearly outside the scope of this overview. Only a brief summary of the most common methods used in PET imaging, with qualitative, general comments, is provided. For a more detailed overview, the interested reader is referred to the overviews offered elsewhere (44,45). The problem of image reconstruction is to calculate the distribution of activity inside an object from the raw data. In PET, these are usually generated in the form of counts for each LOR. Most algorithms first rearrange the data in sinograms, which represent the projection of the object along a parallel, evenly spaced beam in all directions. In the 2D case, image reconstruction is similar to the reconstruction of SPECT data from a parallel-hole collimator. In every single view of the projection data, depth information has been lost, but mathematical analysis shows that if projections are taken from angles covering continuously at least 180 degrees, it is still possible to reconstruct exactly the object, slice by slice, by combining data from all directions. The image of a 3D volume is then obtained by stacking all the 2D slices. In 3D geometry, data from LORs connecting different scanner rings (i.e., for oblique tilt angles) are also acquired. The problem of fully 3D reconstruction is that these LORs cross several transverse slices; thus, it is not immediately possible to process them separately in the same way as each transverse slice. Two different classes of algorithms are used in both 2D and 3D PET image reconstruction: analytic and iterative methods. An example of an analytic algorithm is filtered back projection (FBP), which in its 2D version is analogous to the algorithm used in other imaging modalities. Modifications of the algorithm (e.g., 3D reprojection) were introduced to handle 3D data. A common solution is the use, before reconstruction, of a rebinning algorithm to reorganize oblique into transverse data, which are then processed with 2D algorithms. The simplest approach is single-slice rebinning (SSRB) (46), which assumes that oblique data can be projected directly onto regular transverse slices, but more advanced techniques that rely on less drastic approximations, such as FOurier REbinning (FORE) (47), reduce the loss of axial resolution introduced by rebinning. The main advantage of analytic algorithms, in both 2D and 3D reconstruction, is their speed; their main drawback is that statistical noise in the data is not modeled. Iterative algorithms handle explicitly data noise and also offer the opportunity to model more precisely the geometry of even complex scanners as well as other effects such as attenuation and scatter; however, more precise models imply much longer reconstruction times, which is the main limitation of the technique even in basic applications. Iterative algorithms start from a guess of the image and then use a computer model of the scanner and physics to predict the projection data that such guess would have generated. Comparison to the data actually acquired provides a correction factor, which is applied to the first guess to obtain a second. Iterations are continued until a satisfying image is reached. Further iteration is usually not worth the

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additional time and may be even harmful because excessive iteration eventually results in undesired effects such as divergence and noise amplification. Iterative algorithms differ in how updates are calculated. The most widely used method is the maximum likelihood expectation maximization (MLEM) algorithm (48,49), which estimates the object for which the probability of acquiring the data that were actually acquired is maximum. Execution can be accelerated by different variants of the algorithm, the most popular of which is ordered subset expectation maximization (OSEM) (50). Other algorithms, such as row action maximum likelihood algorithm (RAMLA) (51–53), achieve stable performance through the use of a well-chosen relaxation parameter that forces a gradual and consistent convergence toward a solution for the consistent portion of the data. Current clinical scanners implement both 2D and 3D versions of iterative algorithms. A popular solution is to use a 2D iterative algorithm, typically OSEM, in place of an analytic method after FORE. A more advanced solution is to incorporate in the iterative algorithm (e.g., RAMLA), a model of the 3D geometry. In this sense, this approach provides “fully 3D” reconstruction. Overall, iterative algorithms are credited with better imaging performance than analytic algorithms. Their performance is particularly advantageous in whole-body studies and in low-count situations. However, especially in situations in which computational time is a limiting factor, analytic algorithms still provide a useful alternative. Time-of-Flight Scanners Lines of response are identified from the location of interaction of the two annihilation photons with the detector. Time-of-flight scanners are also capable of detecting the difference in the time of arrival of the two photons, from which it is possible to calculate the location of the annihilation along the LOR. In principle, this would completely locate the event in 3D, and thus altogether eliminate the need for reconstruction. Unfortunately, this is only a theoretical possibility. In fact, to locate the event along the LOR within, say, 5 mm, it would be necessary to detect a time difference of about 30 ps (30 millionths of a millionth of a second). In practice, with scintillators currently available, it is possible to identify time differences about an order of magnitude larger (i.e., about 300 ps), which corresponds to several centimeters—hardly enough to eliminate the need for image reconstruction. However, time information is still helpful. In fact, reconstruction of conventional PET data starts from the sum of events originating on the whole LOR. Therefore, noise propagation is more pronounced when LORs intersect a wide object, as, for example, in large patients. In ToF PET, this sum can be divided in the contributions due to different sections of the LOR, which provides relative containment of the propagation of statistical noise. Accordingly, all other factors being equal, the main advantage of ToF PET is in reduced image noise and the advantage is more significant for large patients. With current technology, thus, it is doubtful that

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ToF PET will offer advantages in pediatric PET due to the small size of the patients.

System Performance This section discusses very briefly some parameters of interest in the evaluation of the performance of PET scanners. Resolution The resolution of PET scanners can be obtained by measuring the size of the reconstructed image of a point source much smaller than the resolution of the scanner. From this definition, it is evident that a small numerical value is desirable. Modern whole-body clinical scanners have a resolution of 4 to 6 mm in the center of the field of view (FoV). Much better values, down to about 1 mm resolution, have been achieved in research scanners specifically designed for small-animal imaging (54,55). However, in clinical studies, images are typically reconstructed to reduce noise, which worsens resolution to about 10 mm. Count Rate The count rate is the rate at which events are acquired. In PET scanners a distinction is made between the rate at which photons are detected individually (singles rate) and the rate at which coincident events are acquired. Clearly, the two are related. In a typical scanner, the singles rate is a factor of about one thousand higher than the coincident count rate. Whereas it is an important performance parameter, the count rate includes all types of event. Because only true events are useful for image reconstruction, some other figure of merit should be used in the determination of the optimal dose. Noise Equivalent Count Rate The performance of a PET scanner is usually characterized with a figure of merit that, unlike the count rate, can also account for the presence of scatter and random coincidences along with true events. This is the noise equivalent count rate (NECR) (56). If T is the rate of collection of true events and R and S are, respectively, the collection rates of random and scatter events, then NECR ∫

T2 T +S+R

(8)

which assumes random correction with smoothing. The NECR has been shown to be proportional to the square of the signal-to-noise ratio in which signal is given by the true events and noise is the combined statistical fluctuation due to noise from all types of event. The NECR is often plotted vs. the activity in the field of view of the scanner or its concentration in a standard phantom. These are the

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Figure 8.10. Sample noise equivalent count rate (NECR) curve of a whole-body clinical scanner (Allegro, Philips Medical Systems). The NECR is plotted vs. the activity concentration present in a 20 ¥ 70 cm (diameter ¥ height) phantom. Total (true + scatter + random) coincident count rate and random coincidences are also shown separately in this example. The typical dose at our institution is 5.18 kBq/cm3 (0.14 mCi/mL).

NECR curves, an example of which is given in Figure 8.10. The NECR usually presents a maximum. The maximum is determined mainly by the rapid increase of the random count rate, also shown in Figure 8.10. Other factors being equal, desirable properties are high values of the NECR occurring at activity levels of interest in clinical practice. The activity corresponding to the maximum NECR provides an indication of the optimal operation point of the scanner. The optimal dose, however, is also determined by other factors not accounted for in the NECR curve, such as the accuracy of corrections for scatter and random events and radiation safety limits. In particular, note that once a significant fraction of the peak NECR is reached, further increase in the activity results only in progressively minor improvements in the NECR, so that the additional dose burden to the patient may not be entirely justified. For these reasons, injection doses are typically lower than the activity corresponding to the peak NECR. These considerations show that NECR curves contain a simple, although not complete, summary of scanner performance. For this reason, NECR curves should be considered cautiously. For example, when the task is lesion detection, a better figure of merit is lesion detectability as assessed in human observer studies. Though it is possible to measure the sensitivity and specificity for the detection of lesions in PET images, these studies require data that are difficult and time-consuming to acquire, and the method of acquiring the data has not yet been standardized. For these reasons, they are not yet part of the standard protocols for the evaluation of the performance of clinical scanners.

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Overview and Performance of Today’s Clinical Scanners Early PET scanners were designed as 2D systems. As solutions for the challenges of 3D imaging were developed (i.e., count rate as well as scatter and randoms correction), scanners with both 2D and 3D capability were introduced. Today, most scanners on the market operate only in 3D. This trend is also connected to the substitution of slow scintillators (mainly BGO and NaI) with significantly faster materials, such as GSO, LSO, and, more recently, LYSO, whose properties are very similar to LSO. Commercial scanners are still based on different light coupling designs, chiefly the block and the pixelated Anger detector configurations. Resolution is directly connected to the size of the crystals used, which is usually in the lower end of the range from 4 to 8 mm. Typical axial FOVs range from 15 to 18 cm. Most scanners currently sold today are sold as PET/CT units. The fluorodeoxyglucose (FDG) scans in Figure 8.9 were acquired on one (Allegro, Philips Medical Systems Cleveland, Ohio) of the wholebody scanners currently installed at the PET center of the University of Pennsylvania. Figure 8.9A shows a 6-year-old girl (18 kg) with a history of neuroblastoma. The image shows no definite evidence of active neoplastic process. The FDG uptake is diffusely increased in the bone marrow due to the administration of colony-stimulating factors, with the exception of the midthoracic to the upper lumbar spine, where uptake is decreased, likely due to radiation therapy. Figure 8.9B shows a 13-year-old girl (52.3 kg) evaluated for possible lymphoma. The image shows two small foci of increased FDG activity in the superolateral aspect of the uterus bilaterally of uncertain etiology. Figure 8.9C shows a 19-year-old man (72.7 kg) with a history of Hodgkin’s disease and a right kidney transplant. Increased uptake in the neck is likely a normal variant of muscle uptake due to contraction. Also, the transplanted kidney is visualized. The rest of the FDG distribution is normal. The absence of focal areas of abnormal FDG uptake suggests the absence of active neoplastic disease. Unattenuated 511-keV photon pairs from the center of the body vary from 20% of all events for the first patient to a little less than 10% in the heaviest. The fraction of scatter events increases with the weight of the patient from about 25% to about 35% for these three patients. Physics Considerations in Small-Patient Imaging The diseases to which PET has been applied for diagnosis and evaluation in adults are infrequent in pediatrics. Nevertheless, in certain applications, pediatric PET is taking up a more important role, specifically in brain imaging (epilepsy) as well as in whole-body imaging (bone tumors, lymphoma, neuroblastoma) (57). To date, no special scanners have been expressly designed for pediatric imaging; only adult scanners are used. The pediatric population covers the range of patient sizes from newborns to young adults. Though the same considerations that apply to adults apply to children, imaging of small patients offers advantages and poses challenges for the optimal use of the instrumentation. The

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most obvious advantage is that in a small patient attenuation and scatter are relatively low. Also, the 3D mode should be particularly competitive for quantitative accuracy because the magnitude of the scatter compensation necessary is relatively lower. Sensitivity is particularly important to keep dose and scan time at a minimum, which may be particularly desirable in this population. On the other hand, energy resolution may be less of a concern because of the reduced need for scatter rejection. Finally, fast timing may not be necessary because of the low activity. Therefore, scanners based on high-sensitivity scintillators may be attractive in pediatrics in spite of their energy and timing resolution. As for the overall geometry of the scanner, a smaller transverse field of view may be sufficient, especially for newborns and infants. Dedicated brain and small animal scanners were developed to take advantage of similar opportunities. It makes sense, then, to accommodate a patient sufficiently small in a brain scanner, which is designed to provide better resolution and higher sensitivity over a smaller and longer field of view than a whole-body scanner. This solution may be practical only for very few patients, likely not enough to justify the acquisition of a special purpose scanner at most institutions.

Conclusion In pediatric PET imaging, the same scanners designed for adult imaging are used successfully. In general, PET image quality depends on the weight of the patient for a given scan time. In lighter patients, attenuation and scatter are minimized, which results in improved image quality. This is often the case in pediatric imaging, especially for younger patients. Alternatively, the improvement in image quality can be traded off for reduced scan time at constant image quality. The main challenge, in particular for the smallest patients, comes from the need for improved resolution and sensitivity, especially when lower tracer concentrations are used to minimize the dose burden to a young population. These needs can be answered with a scanner design with prolonged axial and reduced transverse field of view (and patient port). The result would then be a design similar to the adult brain scanners present at some research institutions. Operation in 3D mode seems particularly appealing again because of the low scatter and random fractions expected in pediatric studies. For the same reason, especially if low levels of activity are preferred for radiation exposure considerations, scintillators with high stopping power may be very competitive compared to less efficient or faster materials, even at the cost of relatively poor energy resolution and timing properties.

References 1. Valk PE, Bailey DL, Townsend DW, Maisey MN. Positron Emission Tomography: Basic Science and Clinical Practice. New York: Springer-Verlag, 2003.

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Chapter 8 Physics and Instrumentation in PET 2. Bendriem B, Townsend DW. The Theory and Practice of 3D PET. New York: Kluwer Academic Publishers, 1998. 3. Krane KS. Introductory Nuclear Physics. New York: Wiley, 1987. 4. Harpen MD. Positronium: review of symmetry, conserved quantities and decay for the radiological physicist. Med Phys 2004;31:57–61. 5. De Beneditti S, Cowan CE, Konneker WR, et al. On the angular distribution of two-photon annihilation radiation. Phys Rev 1950;77:205–212. 6. Levin CS, Hoffman EJ. Calculation of positron range and its effect on the fundamental limit of positron emission tomography system spatial resolution. Phys Med Biol 1999;44:781–799. 7. Evans RD. The Atomic Nucleus. New York: McGraw-Hill, 1955. 8. Surti S, Karp JS, Muehllehner G. Image quality assessment of LaBr3-based whole-body 3D PET scanners: a Monte Carlo evaluation. Phys Med Biol 2004;49:4593–4610. 9. Karp JS, Muehllehner G, Mankoff DA, et al. Continuous-slice PENN-PET: a positron tomograph with volume imaging capability. J Nucl Med 1990;31: 617–627. 10. Adam LE, Karp JS, Daube-Witherspoon ME, Smith RJ. Performance of a whole-body PET scanner using curve-plate NaI(Tl) detectors. J Nucl Med 2001;42:1821–1830. 11. Surti S, Karp JS, Freifelder R, Liu F. Optimizing the performance of a PET detector using discrete GSO crystals on a continuous lightguide. IEEE Trans Nucl Sci 2000;47:1030–1036. 12. Nutt R, Casey M, Carroll LR, Dahlbom M, Hoffman EJ. A new multi-crystal two-dimensional detector block for PET. J Nucl Med 1985;26:P28. 13. Wong WH, Uribe J, Hicks K, Hu GJ. An analog decoding BGO block detector using circular photomultipliers. IEEE T Nucl Sci 1995;42:1095–1101. 14. Moses WW, Derenzo SE. Design studies for a PET detector module using a pin photodiode to measure depth of interaction. IEEE Trans Nucl Sci 1994;41:1441–1445. 15. Casey ME, Eriksson L, Schmand M, et al. Investigation of LSO crystals for high spatial resolution positron emission tomography. IEEE Trans Nucl Sci 1997;44:1109–1113. 16. El Fakhri G, Holdsworth C, Badawi RD, et al. Impact of acquisition geometry and patient habitus on lesion detectability in whole-body FDG-PET: a channelized Hotelling observer study. Presented at IEEE Nuclear Science Symposium and Medical Imaging Conference, Norfolk, VA, 2002. 17. Defrise M, Townsend DW, Bailey D, Geissbuhler A, Michel C, Jones T. A normalization technique for 3D PET data. Phys Med Biol 1991;36:939–952. 18. Bailey DL, Townsend DW, Kinahan PE, Grootoonk S, Jones T. An investigation of factors affecting detector and geometric correction in normalization of 3–D PET data. IEEE Trans Nucl Sci 1996;43:3300–3307. 19. Badawi RD, Lodge MA, Marsden PK. Algorithms for calculating detector efficiency normalization coefficients for true coincidences in 3D PET, Phys Med Biol 1998;43:189–205. 20. Badawi RD, Marsden PK. Developments in component-based normalization for 3D PET. Phys Med Biol 1999;44:571–594. 21. Badawi RD, Ferreira NC, Kohlmyer SG, Dahlbom M, Marsden PK, Lewellen TK. A comparison of normalization effects on three whole-body cylindrical 3D PET systems. Phys Med Biol 2000;45:3253–3266. 22. Carroll LR, Kertz P, Orcut G. The orbiting rod source: improving performance in PET transmission correction scans. In: Esser PD, ed. Emission Computed Tomography: Current Trends. Society of Nuclear Medicine, New York, 1983.

R. Accorsi et al. 23. Huesman RH, Derenzo SE, Cahoon JL, et al. Orbiting transmission source for positron tomography. IEEE Trans Nucl Sci 1988;35:735–739. 24. Daube-Witherspoon M, Carson RE, Green MV. Postinjection transmission attenuation measurements for PET. IEEE Trans Nucl Sci 1988;NS-35:757– 761. 25. deKemp RA, Nahmias C. Attenuation correction in PET using single photon transmission measurement. Med Phys 1994;21:771–778. 26. Karp JS, Muehllehner G, Qu H, Yan XH. Single transmission in volumeimaging PET with a Cs-137 source. Phys Med Biol 1995;40:929–944. 27. Smith RJ, Karp JS. Post-injection transmission scans in a PET camera operating without septa with simultaneous measurement of emission activity contamination. IEEE Trans Nucl Sci 1996;43:2207–2212. 28. Casey ME, Hoffman EJ. Quantitation in positron emission computedtomography. 7. A technique to reduce noise in accidental coincidence measurements and coincidence efficiency calibration. J Comput Assist Tomogr 1986;10:845–850. 29. Badawi RD, Miller MP, Bailey DL, Marsden PK. Random variance reduction in 3D PET. Phys Med Biol 1999;44:941–954. 30. Karp JS, Muehllehner G, Mankoff DA, et al. Continuous-slice PENN-PET— a positron tomograph with volume imaging capability. J Nucl Med 1990; 31:617–627. 31. Cherry SR, Huang SC. Effects of scatter on model parameter estimates in 3D PET studies of the human brain. IEEE Trans Nucl Sci 1995;42:1174–1179. 32. Bergstrom M, Martin W, Pate B. A look at anatomical and physiological brain images. Dimensions Health Serv 1983;60:36. 33. Hoverath H, Kuebler WK, Ostertag HJ, et al. Scatter correction in the transaxial slices of a whole-body positron emission tomograph. Phys Med Biol 1993;38:717–728. 34. Bailey DL, Meikle SR. A convolution-subtraction scatter correction method for 3D PET. Phys Med Biol 1994;39:411–424. 35. Bendriem B, Trebossen R, Frouin V, Syrota A. A PET scatter correction using simultaneous acquisitions with low and high lower energy thresholds. Presented at 1993 IEEE Nuclear Science Symposium and Medical Imaging Conference, San Francisco, CA, 1993. 36. Grootoonk S, Spinks TJ, Sashin D, Spyrou NM, Jones T. Correction for scatter in 3D brain PET using a dual energy window method. Phys Med Biol 1996;41:2757–2774. 37. Adam LE, Karp JA, Freifelder R. Energy-based scatter correction for 3–D PET scanners using NaI(Tl) detectors. IEEE Trans Med Imaging 2000;19: 513–521. 38. Ollinger JM. Model-based scatter correction for fully 3D PET. Phys Med Biol 1996;41:153–176. 39. Watson CC, Newport D, Casey ME, deKemp RA, Beanlands RS, Schmand M. Evaluation of simulation-based scatter correction for 3-D PET cardiac imaging. IEEE Trans Nucl Sci 1997;44:90–97. 40. Accorsi R, Adam LE, Werner ME, Karp JS. Optimization of a fully 3D single scatter simulation algorithm for 3D PET. Phys Med Biol 2004;49: 2577–2598. 41. Levin CS, Dahlbom M, Hoffman EJ. A Monte-Carlo correction for the effect of Compton-scattering in 3-D PET brain imaging. IEEE Trans Nucl Sci 1995;42:1181–1185. 42. Holdsworth CH, Levin CS, Farquhar TH, Dahlbom M, Hoffman EJ. Investigation of accelerated Monte Carlo techniques for PET simulation and 3D PET scatter correction. IEEE Trans Nucl Sci 2001;48:74–81.

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Chapter 8 Physics and Instrumentation in PET 43. Holdsworth CH, Levin CS, Janecek M, Dahlbom M, Hoffman EJ. Performance analysis of an improved 3-D PET Monte Carlo simulation and scatter correction. IEEE Trans Nucl Sci 2002;49:83–89. 44. Lewitt RM, Matej S. Overview of methods for image reconstruction from projections in emission computed tomography. Proc IEEE 2003;91:1588– 1611. 45. Defrise M, Kinahan PE, Michel C. Image reconstruction algorithms in PET. In: Valk PE, Bailey D, Townsend DW, Maisey MN, eds. Positron Emission Tomography: Basic Science and Clinical Practice. New York: SpringerVerlag, 2003:91–114. 46. Daube-Witherspoon ME, Muehllehner G. Treatment of axial data in threedimensional PET. J Nucl Med 1987;28:1717–1724. 47. Defrise M, Kinahan PE, Townsend DW, Michel C, Sibomana M, Newport DF. Exact and approximate rebinning algorithms for 3D PET data. IEEE Trans Med Imaging 1997;11:145–158. 48. Shepp L, Vardi Y. Maximum likelihood reconstruction for emission tomography. IEEE Trans Med Imaging 1982;MI-1:113–122. 49. Lange K, Carson R. EM reconstruction algorithms for emission and transmission tomography. J Comput Assist Tomogr 1984;8:306–316. 50. Hudson HM, Larkin RS. Accelerated image reconstruction using ordered subsets of projection data. IEEE Trans Med Imaging 1994;13:601–609. 51. DePierro AR. On some nonlinear iterative relaxation methods in remote sensing. Matematica Aplicada Computacional 1989;8:153–166. 52. Browne JA, DePierro AR. A row-action alternative to the EM algorithm for maximizing likelihoods in emission tomography. IEEE Trans Med Imaging 1996;15:687–699. 53. Daube-Witherspoon ME, Matej S, Karp JS. Assessment of image quality with a fast fully 3D reconstruction algorithm. In: Siebert JA, ed. 2001 IEEE Nuclear Science Symposium and Medical Imaging Conference. Piscataway, NJ: Institute of Electrical and Electronics Engineers, 2002:M14–12. 54. Jeavons AP, Chandler RA, Dettmar CAR. A 3D HIDAC-PET camera with sub-millimetre resolution for imaging small animals. IEEE Trans Nucl Sci 1999;46:468–473. 55. Tai YC, Chatziioannou AF, Yang YF, et al. MicroPET II: design, development and initial performance of an improved microPET scanner for smallanimal imaging. Phys Med Biol 2003;48:1519–1537. 56. Strother SC, Casey ME, Hoffman EJ. Measuring PET scanner sensitivity— relating count rates to image signal-to-noise ratios using noise equivalent counts. IEEE Trans Nucl Sci 1990;37:783–788. 57. Jadvar H, Connolly LP, Shulkin BL. PET imaging in pediatric disorders. In: Valk PE, Bailey D, Townsend DW, Maisey MN, eds. Positron Emission Tomography: Basic Science and Clinical Practice. New York: SpringerVerlag, 2003:755–774.

9 How to Image a Child by PET–Computed Tomography Sue C. Kaste and M. Beth McCarville

Positron emission tomography (PET)–computed tomography (CT), which merges functional and anatomic imaging, is likely to herald a new generation of imaging modalities. Despite increasing interest and expertise in PET-CT, incorporation of such new technology into any department can be a challenge. Each department has its individual needs, personality, strengths, and weaknesses. The organization and integration of such imaging equipment must reflect these individual institutional and departmental characteristics, plus available supporting resources and the characteristics of patient cohorts. The applicability of PET/PET-CT is well demonstrated in the adult population, particularly for oncologic and seizure imaging. It has only recently been applied in pediatrics, and therefore experience in the logistics and techniques for imaging children and adolescents are limited. Similarly, the diagnostic sensitivity and specificity of PET/PET-CT and its effect on patient management and outcomes are still largely uncharacterized. This chapter addresses several issues raised by pediatric application of PET-CT. It is written primarily from the vantage point of a dedicated tertiary-care pediatric institution. However, it also addresses issues that can be expected to arise when children are scanned in a predominantly adult department. This chapter does not address all concerns, but rather lays a foundation for the implementation of this exciting new technique in the practice of pediatric imaging.

Pre-Scanning Considerations Interaction with Patient and Family Efficient and successful completion of the examination requires the cooperation of the patient and family, proper patient preparation, and relief of patient and family anxiety. An inviting, comfortable, childfriendly environment should greet the patient and family upon arrival to minimize their anxiety. At the time of scheduling, the patient and family should be advised of the pre-scan fasting requirements, adjust121

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ment of potential hypoglycemic medications, the need for quiet rest during the equilibrium phase, the expected length of the examination, and the sharing of results with the appropriate family members. Pre-scan education should be directed at both the parents and the patient. The amount of information that children can understand and their ability to participate in procedures are typically underestimated (1–4). However, children are not small adults, and interactions with them should be age-appropriate (1–4). The family should be instructed in radiation safety, with emphasis on maintaining maximum distance from the patient during the uptake phase. We typically permit one family member to remain with a young child during the uptake phase. However, pregnant family members and siblings should not be present after fluorine-18 fluorodeoxyglucose (18F-FDG) has been administered. If a single adult arrives with the young patient and siblings, care for the siblings may be a matter of urgency. Therefore, the family should be advised to arrange for child care before the appointment, or provisions for such care should be proactively arranged by the institution or department. The same principles of radiation safety must be extended to ancillary personnel, who should also be monitored for radiation exposure. This precaution applies particularly to those in prolonged close proximity to the patient, such as sedation nurses and anesthesiologists. A rotation schedule like that used for nuclear medicine technologists may be needed in some departments. Such provisions depend on the number of PET-CT cases per day, staff availability, and departmental and institutional resources. In some cases, movable clear shields may be used to enhance the protection of personnel and family members from radiation. Scheduling and Logistics Coordination of Related Services Numerous institutional departments and services must coordinate their efforts in order to successfully care for the pediatric patient and obtain the optimal PET-CT imaging. Figure 9.1 shows many of the resource components that must be organized. The key to successful completion of the study is communication and coordination of the many services involved. The role of each component is briefly addressed below. The PET/PET-CT study begins with a request for the examination by the health care provider. The request should include the age of the patient, details about why the examination is needed, pertinent medical history (e.g., allergies, current medications, history of diabetes, surgery), need for sedation/general anesthesia, and whether an interpreter is needed. Upon receipt of the request, the scheduler must identify potential scheduling conflicts (e.g., other imaging studies, clinic appointments, sedation requirements, laboratory tests). The range of services needed and their availability for the individual patient must be identified. Upon verification of the PET/PET-CT appointment, the patient or

S.C. Kaste and M.B. McCarville Interpreter

CT Technologists Nuclear Technologists

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Anesthesia Patient Scheduling

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Figure 9.1. Diagram of the interaction of the multiple departments and personnel necessary for coordination of PET/PET-CT.

family is given the appointment time, preexamination preparation instructions, and contact information should the patient or family have questions. Behind-the-scenes preparation includes the scheduling of a sedation team member or anesthetist, an interpreter if needed, reservation of the uptake room and PET/PET-CT scanner, identification of needed nuclear medicine or CT technologists, and scheduling of a recovery area in the event that sedation or anesthesia is used. When the PET/PET-CT study is scheduled, order details entered into the scheduling system appear on the work schedules of the diagnostic imaging or nuclear medicine department, depending on the institution. This item on the schedule prompts the nuclear medicine technologist to interact with the nuclear pharmacy to ensure that the 18F-FDG dose will be available at the appropriate time. The designated radiologist or nuclear medicine physician responsible for the study reviews the order details and prescribes the patient positioning, anatomic areas to be assessed, and possible use of contrast material. If the information obtained from the PET/PET-CT study is to be used for radiation therapy treatment planning, direct interaction with the designated radiation oncologist and radiation therapy technologist is needed to facilitate PET/PET-CT data acquisition. This interaction is particularly important when PET/PET-CT images are to be electronically merged with information stored in computer programs used to design the radiation therapy treatment plan. The primary health care provider and the institutional pharmacy should be notified of a PET/PET-CT study on an inpatient to allow adjustment of diabetic medications, intravenous fluids, and total parenteral nutrition. In an institution such as ours that has central scheduling and electronic order entry, coordination of some of the resources can be built into the order set for the PET/PET-CT. Similarly, patient preparation

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instructions can be automatically printed at the time of scheduling and given to the patient or appropriate family member. These instructions can be linked to the electronic medical record for the reference of house staff and nursing personnel. In the absence of electronic scheduling, the needed services are usually coordinated by the scheduler, who phones each department to request that the needed services be available at the agreed-upon appointment time. One central person should be responsible for relaying the appointment information to the patient or accompanying family member. Additional scheduling considerations may be necessary when pediatric patients undergo PET/PET-CT imaging in a predominantly adult department. Scheduling adjustments might include specified days of the week for pediatric imaging, a special waiting area with child-appropriate activities, pediatric-oriented informational brochures, and child life personnel who interact with patients and family members. To further minimize patient and family anxiety, consideration should also be given to placement of the intravenous access by pediatric specialists before the patient reports to the imaging department. Diagnostic CT Imaging Performed Simultaneously with PET/PET-CT Contemporary PET-CT units merge state-of-the-art CT and PET elements, allowing routine diagnostic CT imaging and PET scans to be performed independently of each other. In our institution, PET-CTs take priority over routine diagnostic CTs on the PET-CT unit. However, any unscheduled table time on the PET-CT unit may be used for routine CTs, biopsies, radiation therapy planning, etc. Such prioritization varies among institutions and depends on the number of CT scanners, the number of PET-CT scanners, and the number and types of cases. Similarly, scheduling of imaging for clinical management, as opposed to studies driven by research protocols, reflects the caseload of the institution. The level of demand for PET-CT studies shortly after installation of our equipment allowed the use of the PET-CT unit for both a PET-CT and a diagnostic CT on the same patient, when so ordered. The orders were designed so that the CT could be ordered within the PET-CT order; it was not necessary to schedule them separately. The two studies could be completed within a single 60-minute appointment time. This scheduling method made efficient use of the imaging table, shortened patient visits, minimized patient inconvenience, and averted any need for multiple administration of sedation or anesthesia. The imaging department member responsible for the PET-CT would prescribe the studies in such a way as to minimize radiation exposure to the patient and optimize the information obtained. Low-dose CT parameters are typically used for the attenuation-correction CT, and standard CT imaging parameters are used for the diagnostic study. However, a diagnostic-quality CT scan using a higher milliamperesecond (mAs) setting than routinely used for the attenuation-correction CT can be used for used for PET-CT and eliminates the need to perform

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two separate CT scans. If needed, display field of view (DFOV) can retrospectively be changed. An additional 10 to 15 minutes of postprocessing time on the system console is needed to convert the image data into an acceptable diagnostic CT. This method would typically include the oral administration of contrast material before the attenuationcorrection CT is performed. Intravenous contrast material would be administered during the attenuation-correction CT. Like others, we have found that the intravenous nonionic contrast and low-density oral contrast media used with diagnostic CT are compatible with PET-CT (4–10). Patients and parents can be confused by the need to maintain glucose restriction when diagnostic CTs are coordinated with PET-CT. We find that both intravenous (IV) and oral contrast agents used for diagnostic CTs can be used in pediatric PET-CT without compromising the PETCT study. In fact, as others have reported (4,5), IV and oral contrast can improve interpretation of the PET-CT, particularly in studies of small children with limited retroperitoneal fat and in differentiation of vessels from lymph nodes and tumors that lack 18F-FDG avidity in the mediastinum and neck. However, oral contrast agents must be taken with sugar-free beverages. We provide a choice of flavored sugar-free mixes to our patients. In a department such as ours, where CT and PETCT technologists are shared and the examinations are performed in adjacent suites, sugar-free beverage mixes for oral contrast agent could be offered to all patients undergoing CT, whether or not PET-CT is also scheduled. Such an approach might minimize patient confusion but places the burden of dispensing the beverages on the technologists and the department. The logistics of such a practice depend on the department and the institution. Arm position also becomes an issue when the two types of studies are combined; this consideration is discussed below (see Patient Positioning). With increasing demand for PET-CT studies, we will likely begin performing on the PET-CT unit only those diagnostic CT studies that require sedation or anesthesia. All others will be scheduled on the standard diagnostic CT unit. The diagnostic CT is most often performed as a completely separate study after completion of the PET/PET-CT. This method optimizes use of the PET/PET-CT scanner for its specialized purpose, allows the patient to rest between studies, and allows more flexibility in the administration of oral and intravenous contrast. Patient Preparation Forcing of sugar-free beverages or intravenous fluids before administration of 18F-FDG can help to clear background avidity and improve image interpretation. Oral administration of fluids must be coordinated with the need for sedation or anesthesia (discussed below). To minimize competition between physiologic glucose and 18F-FDG, patients are typically instructed to fast overnight for early morning studies and for a minimum of 4 hours before studies performed later

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in the day. Departments may request an NPO (nothing by mouth) period of 4 to 8 hours before 18F-FDG administration (4,11–16). The difference largely reflects patient age and the need for sedation or general anesthesia. Adherence to an NPO instruction can be particularly challenging in pediatrics. Despite the best efforts of parents and health care providers, pediatric patients seem to have an endless hidden repository of sugarladen treats. Although a single gummy worm may not adversely affect FDG uptake in an adolescent, a bag of jelly beans can potentially block FDG uptake in a 6-year-old, thus prompting cancellation of the study and the possible waste of the FDG dose. When studies are performed on inpatients, similar coordination and education should be implemented with the nursing staff, pharmacy, sedation team, and primary care service. There is a real possibility that an inpatient may arrive in the nuclear medicine suite while receiving intravenous fluids, not uncommonly with added dextrose [e.g., dextrose 5% in water (D5W) with 50 g added dextrose, total parenteral nutrition, etc.]. For this reason, the need for fasting and avoidance of glucose-laden solutions must be communicated to the primary health care service, nursing staff, and pharmacy. Further, management of serum glucose levels in diabetics may be more complicated than adherence to NPO restrictions. Modification of patient diet or medication should be coordinated by the responsible service or individual in collaboration with nuclear medicine, the patient, technologists, and other ancillary personnel. Medications and liquids that might not readily be appreciated as containing sugars include diphenhydramine (Benadryl) liquid and cough medicines flavored with sugar syrups. Direct questioning of the patient or accompanying adult about the use of such medications is thus necessary. Serum glucose should be assayed before the radioisotope is injected. Typically, a serum glucose concentration below 200 mg/dL is adequately low to allow FDG uptake into metabolically active tissues. Some departments prefer to maintain a glucometer in the nuclear medicine suite and incorporate a serum glucose check into the pre-scan preparation. In other institutions, serum glucose is determined in the main laboratory and expeditiously reported to nuclear medicine before FDG injection. Uptake Phase During the uptake phase (after 18F-FDG injection and prior to imaging), the patient should rest quietly in a warm, nonthreatening environment designed to allay anxiety (Fig. 9.2). A nonpregnant parent, guardian, or health care provider may sit with young children but must adhere to radiation protection guidelines. If the patient is to undergo imaging of the axial and appendicular body, then quiet resting activity may be allowed. Such activity includes watching an age-appropriate video, listening to a story, or listening to music. It can be quite a challenge to keep a toddler or young child at quiet rest for up to an hour after injec-

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Figure 9.2. The PET/PET-CT uptake room should be fully furnished, comfortable, and nonthreatening for the patient and accompanying adult. Note the wall-mounted television. A ceiling-mounted video camera by which the patient is constantly monitored is located in the corner opposite the television.

tion; even such seemingly negligible activity as chewing gum, talking, or playing video games may complicate FDG interpretation. If the patient is to undergo PET/PET-CT imaging of the brain, then any stimulation of the central nervous system should be kept to a bare minimum. The room should be darkened, quiet, and soothing. If possible, eye shields should be used to prevent visual stimulation, which can prompt occipital activity. Similarly, videos, music, and talking are avoided. Uptake of 18F-FDG by thermogenic “brown fat” can complicate image interpretation. The uptake of 18F-FDG by brown fat has been attributed to the ambient outdoor temperature (17–19). It is seen more often in females than males and occurs more often in children and young adults than in older patients (17–19). Rats exposed to a cold room for several hours prior to imaging showed stimulation of 18F-FDG uptake (19). The effect of brief exposure to cool or cold temperatures in humans has not been verified. However, this finding in rats suggests that a warm equilibrium room or possibly the use of an extra blanket or heavier clothing may minimize the 18F-FDG avidity of brown fat. Such uptake can potentially complicate imaging interpretation, particularly when PET is performed without correlative CT imaging (11,12,17–21). For patients who are extremely restless or anxious, quiet rest may be facilitated by the use of anxiolytic drugs during the equilibrium phase. We do not typically administer such agents. However, if a patient is

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noted to be particularly restless during the equilibrium phase or scanning at our institution, or if children have a prior history of anxiety during studies at other institutions, anxiolytics are considered for future studies. Patient monitoring begins with the registration of the patient in the imaging department and continues from the time of injection until completion of post-scan recovery. At our institution, the patient is injected with 18F-FDG in the uptake room. This room is constantly monitored by a video camera, which allows real-time viewing of the patient and the room from the PET/CT scanning console area directly across the hall.

Scanning of the Patient Timing of Imaging Positron emission tomography imaging should be timed in coordination with the chemotherapy cycles to prevent their affecting the results of studies. Imaging done for staging purposes should be performed before induction chemotherapy or other therapeutic intervention. The timing of follow-up imaging may be more variable. However, we have found that the optimal time to assess the response to therapy is probably just before the next course of therapy. This strategy minimizes any potential “flare” response from chemotherapy, granulocyte colony-stimulating factor, radiation therapy, or even radiofrequency ablation. A flare response typically occurs within 2 days of chemotherapy or radiation therapy. Similarly, postoperative changes are most apparent during the first several weeks after surgery. Therefore, we prefer to wait at least 2 to 3 weeks after surgery before performing follow-up imaging. Standardization of technique is important to allow the comparison of studies, particularly when response is to be quantified by imaging. As many patients with cancer undergo serial imaging for assessment of treatment response, a log of prior imaging parameters or inclusion of these parameters in the dictated report is helpful to ensure consistent imaging. These include radiopharmaceutical dose, equilibration time, two- or three-dimensional image acquisition, patient height and weight, and patient positioning. One potentially overlooked aspect of standardization is synchrony of the PET-CT clock with the clock used to determine dose assay times. The “hot lab” clock is typically used to calculate the dose of 18F-FDG at the time of injection, and the clock in PET-CT is used to determine the time that scanning is initiated. Dose quantification for the study at the time of scanning will be inaccurate if these two clocks are not synchronized. Immobilization of the Patient Patient immobilization is paramount in obtaining well-registered PET/CT studies with minimal motion artifact. Difficulty in maintain-

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ing immobilization is dependent on several factors: child age, medical condition, pain level, physical positioning of the patient on the scanning table, and length of time to complete the study (which is partly dependent on patient size). There are several standard immobilization techniques that may be used with PET/CT. Swaddling may be considered for very young or small infants and children, particularly for short studies. This technique may be particularly effective if the scanning time can be coordinated with the patient’s usual nap time. Immobilization is optimized by ensuring that the patient is comfortable and warm and that any potential pain has been controlled. More sophisticated immobilization techniques include special cushions similar to those used in radiation oncology: the child is placed on a cushion that is filled with tiny plastic balls and is fitted to the contour of the patient by vacuum extraction. For more cooperative children, patient positioning may be maintained by using sandbags, rolled towels, or pillows held in place by strategically placed strips of tape or Velcro straps. Certainly immobilization is optimized when the patient is sedated under general anesthesia. In such cases, the anesthesiologist is in control of the patient and positioning must adhere to the needs of the anesthesiologist in the interest of patient safety. Sedation and General Anesthesia As with other lengthy pediatric procedures, sedation or general anesthesia may be necessary to complete the PET-CT examination. This is particularly true when imaging very young children who cannot cooperate, those who are mentally impaired, and for the few who demonstrate claustrophobia (11). For some patients, adequate pain control may be all that is needed to complete the study. Our practice is to employ sedation or anesthesia only for the imaging phase of the examination. Rarely, sedation may be needed during the equilibrium phase as well, but such a practice considerably extends the sedation/anesthesia time. We calculated that 11.3% (16/142) of patients who underwent PETCT at our institution during the months of September through November 2004 received sedation or anesthesia. We performed eight studies in children aged 0 to 4 years, 28 studies in 5- to 10-year-old children, 74 studies in 11- to 18-year-olds, and 32 studies in patients older than 18 years. Of these, 10 patients aged 22 months to 7 years received intravenous sedation. General anesthesia was administered to five patients aged 23 months to 20 years. One additional patient received intravenous medication for pain control. The preferred method of sedation/anesthesia varies by institution, department, resources, and patient demographics; detailed discussion is beyond the scope of this chapter. However, it should always be administered according to the published guidelines of the American Academy of Pediatrics and the American Society of Anesthesiologists (22,23). At our institution, sedation/anesthesia falls under the auspices

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of the Department of Anesthesia. Under the direction of anesthesiologists or sedation physicians, nurse anesthetists and members of the nursing sedation team assess the patient prior to sedation and administer the sedation, or in the case of nurse anesthetists, general anesthesia. They monitor the patient throughout the examination until full recovery. Other potential mechanisms for patient care and administration of sedation/anesthesia include management by a sedation pediatrician dedicated solely to this task or by the attending pediatrician, radiologist, intensivist, or emergency room physician. Regardless of the mechanism for managing the patient under sedation/anesthesia, qualified personnel whose only responsibility is the care and safety of the patient must be in attendance throughout the study. The need for sedation/anesthesia affects study scheduling, the need for supportive staff and resources, and the use and timing of oral contrast administration. We have strict NPO requirements designed according to the practice guidelines of the American Academy of Pediatrics and the American Society of Anesthesiologists (22,23) that prohibit oral contrast ingestion less than 2 hours prior to sedation. These patients may require separate appointments for PET/PET-CT and a diagnostic CT for which opacification of the gastrointestinal tract is needed. We make every effort to minimize the number of potential sedations, contrast administrations, and appointments for the patient while optimizing the use of imaging and staffing resources. However, patient imaging must be managed on a case-by-case basis as discussed above. Patient Positioning The standard position for PET imaging is the position of comfort with the patient supine and arms at the sides or over the head if the patient can tolerate the position. If the primary site of interest is in the head or neck, then the arms should be placed alongside the torso. However, this position causes significant streak artifacts on the CT images, often limiting the utility of the images. This is particularly problematic when a diagnostic CT and PET-CT are combined in a single study. If the arms are positioned over the patient’s head, then additional imaging stations are required to fully image the upper extremities in total body PET/PET-CT studies. This position is also difficult for patients to maintain during the prolonged PET imaging phase of the study. In such cases, positioning pads or cushions may be helpful. A possible alternative is to lay the patient’s arms across the abdomen; however, this position is more difficult to accurately reproduce on subsequent studies. Arm positioning is a particular issue when the primary disease—or metastatic site—is in the upper extremity. The positioning of the patient is also dictated by the need for sedation/anesthesia, which requires that the airway and the ability to monitor vital signs be given priority. As with any procedure, the physical condition of the patient plays a significant part in positioning. This can be particularly challenging in young or lightly sedated children.

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The patience and creativity of the technologists or parents in working with the patient are often the key to successful imaging. One aspect of positioning that might not be readily apparent is the alignment of the patient positioning for the PET/PET-CT study with the position used for radiation therapy. This positional coordination allows improved merging of image data with the treatment planning data. It may be necessary to scan patients in the prone position or on the positioning cushions as done for administration of therapeutic radiation. Therefore, the imaging team should interact with the radiation oncology team. Scanning Sequence Whether a whole-body study (vertex to toes) or a targeted study (e.g., head, torso, pelvis) is performed should be decided by the information needed to care for the patient. In many cases, a PET/PET-CT study is used for tumor staging. In such cases, detection of distant metastatic disease is important for selecting the appropriate treatment strategy. In other cases, determination of the response of a primary brain tumor or the presence of residual disease in a site of previous surgery or radiofrequency ablation may entail a study limited to the area of interest. Tracer activity in a full bladder can cause significant reconstruction artifacts and may obscure important pathology. To prevent problems caused by the bladder filling between the time scanning is initiated and the time the pelvis is imaged, we image the pelvis first and then scan cephalad through the head in the first set of acquisitions. The rest of the body (pelvis through legs) is scanned in the second set of acquisitions. Between the two sets of acquisitions, the patient is able to void if necessary. Although this method of scanning reduces artifact caused by a distended, radioisotope-filled bladder, it adds 25 to 30 minutes to the appointment. An alternative method is to use bladder catheterization with gravity drainage. The bladder catheter should be placed prior to imaging but after the child has been sedated/anesthetized to minimize trauma to the patient. If the catheter is placed at a later time during the procedure, the remaining sedation may be inadequate to maintain the child’s comfort. A bladder catheter may be needed for children who are to receive sedation/anesthesia, as such medications predispose the patient to bladder activity (11). To avoid catheter artifact, a drainage catheter should be long enough to position the drainage bag outside of the imaging field. Technologists’ Roles State mandates regulating the licensing and handling of radiopharmaceuticals vary to a certain degree and should be consulted during planning for PET and PET-CT. The roles of the CT technologist and the nuclear medicine technologist must be addressed by each institution. The interest and skills of the available technologists, staffing limitations, and physical location of the equipment, together with

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compliance with regulatory mandates, help to define technologists’ roles. In some institutions, staffing and familiarity with the operation of a CT scanner may dictate that the CT technologist perform the actual scanning procedure after radiopharmaceutical injection by the nuclear medicine technologist. In other institutions, the nuclear medicine technologists learn CT scanning techniques and are responsible for completion of the entire study. There are currently no formalized specialty registries for certification of PET-CT technologists. However, the American Society of Radiologic Technologists (ASRT) and the Society of Nuclear Medicine Technologist Section (SNMTS) are collaboratively designing a supplementary training curriculum that will address the needs of practicing technologists who wish to obtain competency in this new modality. The best source of information on local regulatory mandates and legislation is the Radiation Safety Office under which the PET/PET-CT facility operates and under which the technologists practice. Additional useful Web sites include those of the Nuclear Regulatory Commission (http://www.nrc.gov), the American Society of Radiologic Technologists (http://asrt.org), the Society of Nuclear Medicine (http://snm.org), the American Registry of Radiologic Technologists (http://www.arrt.org), and the Nuclear Medicine Technology Certification Board (http://www.nmtcb.org). When we began PET-CT imaging, the nuclear medicine technologists accompanied the patient to the uptake room, injected the radiopharmaceutical, and transferred monitoring of the patient and completion of the study to the CT technologists. After the appropriate equilibrium time, the patient would be instructed to void and transported across the hall to the PET-CT scan room by the CT technologist, who would complete the patient scanning and image processing. If a diagnostic CT was also ordered, it would be completed during the same appointment time. After scanning was complete, the patient was dismissed by the CT technologists or observed by the sedation/anesthesia team until recovery. Currently, our nuclear medicine technologists are responsible for all phases of the PET-CT examination. If a diagnostic CT has also been ordered, then one of the CT technologists performs that study separately. A diagnostic CT is currently ordered with PET/PET-CTs in approximately 80% of cases in our institution. This number varies by institution. Transfer of technologist responsibility and transfer of patients between scanners is facilitated in our department by design of the CT imaging suite. The dedicated CT scanner and the PET-CT scanner occupy adjacent rooms with a shared console area.

Conclusion Positron emission tomography–computed tomography is an exciting imaging modality that merges functional and anatomic information and that is expected to refine assessment of disease and response to

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therapy. Though in its infancy, particularly for imaging children and adolescents, it shows great promise in the detection and monitoring of disease. Special logistical procedures should be implemented for the care, safety, and monitoring of pediatric patients. This chapter serves as a starting point for planning and implementing PET-CT imaging in pediatrics.

References 1. Tates K, Meeuwesen L. “Let mum have her say”: Turntaking in a doctorparent-child communication. Counseling 2000;40:151–162. 2. Rushforth H. Practitioner review: communicating with hospitalised children: review and application of research pertaining to children’s understanding of health and illness. J Child Psychol Psychiatry 1999;40:683–691. 3. Jay SM, Elliott CH, Ozolons M, et al. Behaviourial management of children’s distress during painful medical procedures. Behav Res Ther 1985;23:513–520. 4. Borgwardt L, Larsen HJ, Pedersen K, et al. Practical use and implementation of PET in children in a hospital PET centre. Eur J Nucl Med Molec Imag 2003;30(10):1389–1397. 5. Dizendorf EV, Treyer V, von Schulthess GK, et al. Application of oral contrast media in coregistered positron emission tomography-CT. AJR 2002;179:477–481. 6. Antoch G, Freudenberg LS, Strattus J, et al. Whole-body positron emission tomography-CT: optimized CT using oral and IV contrast materials. AJR 2002;179:1555–1560. 7. Nakamoto Y, Chin BB, Kraitchman DL, et al. Effects of nonionic intravenous contrast agents at PET/CT imaging: phantom and canine studies. Radiology 2003;227(3):817–824. 8. Cohade C, Osman M, Nakamoto Y, et al. Initial experience with oral contrast in PET/CT: phantom and clinical studies. J Nucl Med 2003;44(3): 412–416. 9. Cohade C, Wahl RL. Applications of positron emission tomography/computed tomography image fusion in clinical positron emission tomography—clinical use, interpretation methods, diagnostic improvements. Semin Nucl Med 2003;33(3):228–237. 10. Roberts EG, Shulkin BL. Technical issues in performing PET studies in pediatric patients. J Nucl Med Technol 2004;32:5–9. 11. Shulkin BL. PET imaging in pediatric oncology. Pediatr Radiol 2004;34(3): 199–204. 12. Kaste SC. Issues specific to implementing PET-CT for pediatric oncology: what we have learned along the way. Pediatr Radiol 2004;34(3):205–213. 13. Roberts EG, Shulkin BL. Technical issues in performing PET studies in pediatric patients. J Nucl Med Technol 2004;32(1):5–9. 14. Jadvar H, Connolly LP, Shulkin BL, et al. Positron-emission tomography in pediatrics. Nucl Med Annu 2000;53–83. 15. Wahl RL. Principles of cancer imaging with fluorodeoxyglucose. In: Wahl RL, Buchanan JW, eds. Principles and Practice of Positron Emission Tomography. Philadelphia: Lippincott Williams & Wilkins, 2002:100–110. 16. Bar-Shalom R, Yefremov N, Guralnik L, et al. Clinical performance of PET/CT in evaluation of cancer: additional value for diagnostic imaging and patient management. J Nucl Med 2003;44:1200–1209.

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Chapter 9 How to Image a Child by PET–Computed Tomography 17. Yeung HWD, Grewal RK, Gonen M, et al. Patterns of 18F-FDG uptake in adipose tissue and muscle: a potential source of false-positives for PET. J Nucl Med 2003;44:1789–1796. 18. Cohade C, Mourtzikos KA, Wahl RL. “USA-Fat”: prevalence is related to ambient outdoor temperature—evaluation with 18F-FDG PET/CT. J Nucl Med 2003;44:1267–1270. 19. Cohade C, Osman M, Pannu HK, et al. Uptake in supraclavicular area fat (“USA-Fat”): description on 18F-FDG PET/CT. J Nucl Med 2003;44(2): 170–176. 20. Tatsumi M, Engles JM, Ishimori T, et al. Intense (18)F-FDG uptake in brown fat can be reduced pharmacologically. J Nucl Med 2004;45(7):1189–1193. 21. Hudson MM, Krasin MJ, Kaste SC. PET imaging in pediatric Hodgkin’s lymphoma. Pediatr Radiol 2004;34(3):190–198. 22. American Academy of Pediatrics: Committee on Drugs. Guidelines for monitoring and management of pediatric patients during and after sedation for diagnostic and therapeutic procedures. Pediatrics 1992;89:1110– 1117. 23. American Society of Anesthesiologists: Task Force on sedation and analgesia by non-anesthesiologists. Practice guidelines for sedation and analgesia by non-anesthesiologists. Anesthesiology 2002;96:1004–1017.

10 Coincidence Imaging Girish Bal, Stefaan Vandenberghe, and Martin Charron

The concept of using gamma cameras to detect the 511 keV g rays, arising from the annihilation of a positron, was first implemented by H.O. Anger in the late 1950s (1–4). These cameras were capable of acquiring planar images of low-energy single photons as well as acquiring tomographic images of 511-keV photons in the coincidence mode. In the absence of a collimator, the resolution and sensitivity of the images obtained using the coincidence mode was far superior to that obtained using a collimated single photon emission computed tomography (SPECT) system. However, due to the limited count rate capability, slow computational speed, and lack of algorithms to process the acquired coincidence data, coincidence imaging was not widely used for clinical applications. Further, the limited availability of the fast decaying positron emitting tracers, coupled with limited reimbursement from the insurance companies, temporarily halted the development of gamma camera–based positron emission tomography (GCPET) systems (5,6). In the mid-1990s, significant improvements were made to overcome the count rate limitations of the sodium iodide [NaI(Tl)]-based gamma cameras (7–11). These improvements coupled with the establishment of regional distribution centers for fluorine-18 fluorodeoxyglucose (FDG) resulted in renewed interest in GCPET as a cost-effective alternative to dedicated positron emission tomography (PET) systems. Furthermore, the relatively long half-life of FDG, compared to other positron tracers, enabled longer acquisition times so as to obtain statistically significant counts for a faithful reconstruction. The convenience of performing both single photon and positron imaging on the same scanner made GCPET an attractive option, in terms of cost-effectiveness, for many nuclear medicine departments around the world.

Single Photon Emission Computed Tomography Imaging of 511-keV Photons Apart from the fact that GCPET can be used to image the biodistribution of positron tracers in coincidence mode, they can also be used to image the 511-keV photons as single photons using an ultra-high 135

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energy collimator. In this imaging protocol, the annihilation photons are detected as single photons that successfully pass through the collimator holes. To compromise between the ability to detect a sufficient number of 511-keV photons and at the same time achieve reasonable spatial resolution, collimators with thick lead septa and long bores were designed. For example, an ultra-high energy parallel-hole collimator consisting of hexagonal holes with a diameter of 5.08 mm (flat side to flat side), septal thickness of 3.43 mm, and bore length of 77 mm was designed for FDG-SPECT imaging using a three-head gamma camera (12) (Fig. 10.1). This system had a spatial resolution of about 11 to 15 mm full width half maximal (FWHM) for a point source placed at a distance of 10 cm from the collimator and a sensitivity of about two counts per second per microcurie (mCi) per detector. In spite of the thick septa, some septal penetration is inevitable, resulting in a loss of resolution as well as an increase in the background activity in the projection data. This background tends to degrade the contrast of the reconstructed image, thereby degrading the detectability of lesions smaller than 2 to 3 cm (13,14). Hence, 511-keV SPECT is

trigger detection discriminator

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coincidence circuit |t1–t2|5 cm; no nodal or systemic metastases (G1T2N0M0) IIA Moderate-grade sarcoma; tumor £5 cm; no nodal or systemic metastases (G2T1N0M0) IIB Moderate-grade sarcoma; tumor >5 cm; no nodal or systemic metastases (G2T2N0M0) IIIA High-grade sarcoma; tumor £5 cm; no nodal or systemic metastases (G3T1N0M0) IIIB High-grade sarcoma; tumor >5 cm; no nodal or systemic metastases (G3T2N0M0) IVA Any grade sarcoma; any tumor size; with regional node metastases; no systemic metastases (any G, any T, N1M0) IV Any grade sarcoma; any tumor size; any nodal status; with systemic metastases (any G, any T, any N, M1)

M.P. Hickeson

Early detection of recurrence allows a larger variety of treatment options and results in better prognosis than late detection of recurrence. Therefore, early detection of recurrence is important for the treatment of sarcomas. There has been a significant evolution in the treatment of soft tissue sarcoma. For aggressive tumors, surgical resection is the method of choice of local control. For sarcomas involving the limbs, limbsparing procedures can be appropriately performed by chemotherapy in the neoadjuvant (presurgical) setting. The primary objective is tumor eradication. However, the response to therapy varies considerably with different tumors. Identification of resistant or nonresponding tumors early or immediately after initiation of therapy would be most advantageous, so that an alternative, potentially more effective, treatment can be instituted in a timely manner. Toxicities from ineffective therapy can also be prevented. Unlike anatomic imaging modalities, which assess tumor response by size criteria, PET assesses the metabolic activity of tumors. Studies have shown that therapyinduced anatomic changes lag behind metabolic changes of the tumor (28). One specific example that FDG-PET has demonstrated its utility for early prediction of response to therapy is with the treatment of gastrointestinal intestinal stromal tumors (GISTs), which are tumors of mesenchymal origin arising from the gastrointestinal tract. A significant percentage of these tumors have an exceptional response to the tyrosine kinase inhibitor, imatinib mesylate (Gleevec/Glivec). Fluorodeoxyglucose-PET has been shown to be an early indicator of tumor response to treatment (Figs. 16.1 to 16.3) (29). In all responders, a significant decrease of FDG uptake was observed as early as 24 hours after the administration of a single dose of Gleevec. Subsequent studies have indicated that FDG-PET is the imaging modality of choice for early

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Figure 16.1. Patient has a tenosynovial cell sarcoma in the left knee, which is demonstrated on the baseline fluorodeoxyglucose–positron emission tomography (FDG-PET) scan (A). The posttherapy FDG-PET scan (B) demonstrated a complete metabolic response to therapy.

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Figure 16.2. Patient with gastrointestinal stroma tumor of the stomach who had undergone FDG-PET study after chemotherapy. The transaxial (A), sagittal (B), and coronal images (C) are shown and demonstrate a large mass with no evidence of FDG metabolism (arrows) with the exception of a focus of hypermetabolism at its stalk (arrowheads), which was proven to be residual tumor.

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Figure 16.3. Partial metabolic response in this patient with history of gastrointestinal stromal tumor of the rectum who had undergone FDG-PET study prior to (A, narrow arrows) and 3 weeks after initiation of therapy (B, wide arrows).

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Table 16.2. Tumor response using FDG-PET with the European Organization for Research and Treatment of Cancer (EORTC) criteria Response Progressive metabolic disease Stable disease

Partial metabolic response Complete metabolic response

Definition Increase in FDG tumor SUV of equal or greater than 25% within the tumor region as compared to the baseline study or appearance of new FDG uptake in metastatic lesions Increase in tumor FDG uptake of less than 25% or a decrease of less than 15% of FDG uptake within the tumor region as compared to the baseline study Reduction of at least 15% of FDG uptake within the tumor as compared to the baseline study Complete resolution of FDG uptake within the tumor

prediction of response to therapy for a patient with GIST treated with Gleevec (30–32). The metabolic response of tumor from therapy can be defined using the European Organization for Research and Treatment of Cancer (EORTC) criteria (Table 16.2) (33). Hain et al. (34) studied the findings of 16 patients with amputation in either the upper or lower limb on FDG-PET. Diffuse hypermetabolism at the amputation stump up to 18 months postsurgery is a common finding. However, focal hypermetabolism may be associated with a pressure area if there is clinical evidence of skin breakdown at that site. However, if there is no evidence of localized skin breakdown at the site of focal hypermetabolism, then the finding indicates a recurrence, and a skin biopsy is indicated. Kole et al. (35) have also reported a 93% sensitivity of FDG-PET for the detection of recurrence of soft tissue sarcomas in 14 patients. Prognostic Information A noninvasive method to determine tumor regional glucose metabolism is with FDG-PET. Eary et al. (36) reported that FDG-PET provides independent prognostic information in a retrospective analysis of 209 patients with sarcomas. They have shown that the risk of death increases by approximately 60% for each doubling of the maximal baseline lesion SUV. Schuetze et al. (37) have demonstrated that soft tissue sarcomas with a pretreatment SUV of greater than 6.0 are associated with a higher risk of recurrence and of mortality than those with SUV of less than 6.0. Another negative prognostic finding provided by FDGPET is lack of reduction in SUV of the lesion with therapy (Fig. 16.4) (37). In general, FDG tumor activity is positively associated with the metabolic activity, and tumor metabolic activity is positively associated with aggressiveness. Aggressive tumors have a worse prognosis than those with less aggressive histology.

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A

B

Figure 16.4. Evidence of progression in this patient with an aggressive metastatic sarcoma of the left foot who had undergone FDG-PET study prior to (A) and after completing chemotherapy (B). The baseline SUV was 13.9; this increased to 18.2 on the posttherapy scan, which indicates a poor prognosis.

Conclusion Positron emission tomography with 18F-fluorodeoxyglucose has been shown to have potential value in the evaluation of primary malignant lesions, for staging, for the response to treatment and detection of recurrence, and for prognostic information.

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References 1. Landis SH, Murray T, Bolden S, Wingo PA. Cancer statistics, 1998. CA Cancer J Clin 1998;48(1):6–29. 2. Marina NM, Krance R, Ribeiro RC, Crist WM. Diagnosis and treatment of the most common solid tumors in childhood. Prim Care 1992;19(4): 871–889. 3. Nijhuis PH, Schaapveld M, Otter R, Molenaar WM, van der Graaf WT, Hoekstra HJ. Epidemiological aspects of soft tissue sarcomas (STS)—consequences for the design of clinical STS trials. Eur J Cancer 1999;35(12): 1705–1710. 4. Zagars GK, Ballo MT, Pisters PW, Pollock RE, Patel SR, Benjamin RS. Prognostic factors for disease-specific survival after first relapse of soft-tissue sarcoma: analysis of 402 patients with disease relapse after initial conservative surgery and radiotherapy. Int J Radiat Oncol Biol Phys 2003;57(3): 739–747. 5. Schwarzbach MH, Dimitrakopoulou-Strauss A, Willeke F, et al. Clinical value of [18–F] fluorodeoxyglucose positron emission tomography imaging in soft tissue sarcomas. Ann Surg 2000;231(3):380–386. 6. Watanabe H, Shinozaki T, Yanagawa T, et al. Glucose metabolic analysis of musculoskeletal tumours using 18-fluorine-FDG PET as an aid to preoperative planning. J Bone Joint Surg Br 2000;82(5):760–767. 7. Griffeth LK, Dehdashti F, McGuire AH, et al. PET evaluation of soft-tissue masses with fluorine-18 fluoro-2-deoxy-D-glucose. Radiology 1992;182(1): 185–194. 8. Schulte M, Brecht-Krauss D, Heymer B, et al. Fluorodeoxyglucose positron emission tomography of soft tissue tumours: is a non-invasive determination of biological activity possible? Eur J Nucl Med 1999;26(6):599–605. 9. Lucas JD, O’Doherty MJ, Cronin BF, et al. Prospective evaluation of soft tissue masses and sarcomas using fluorodeoxyglucose positron emission tomography. Br J Surg 1999;86(4):550–556. 10. Kern KA, Brunetti A, Norton JA, et al. Metabolic imaging of human extremity musculoskeletal tumors by PET. J Nucl Med 1988;29(2):181–186. 11. Lucas JD, O’Doherty MJ, Wong JC, et al. Evaluation of fluorodeoxyglucose positron emission tomography in the management of soft-tissue sarcomas. J Bone Joint Surg Br 1998;80(3):441–447. 12. Lodge MA, Lucas JD, Marsden PK, Cronin BF, O’Doherty MJ, Smith MA. A PET study of 18FDG uptake in soft tissue masses. Eur J Nucl Med 1999; 26(1):22–30. 13. Ferner RE, Lucas JD, O’Doherty MJ, et al. Evaluation of (18)fluorodeoxyglucose positron emission tomography ((18)FDG PET) in the detection of malignant peripheral nerve sheath tumours arising from within plexiform neurofibromas in neurofibromatosis 1. J Neurol Neurosurg Psychiatry 2000;68(3):353–357. 14. Adler LP, Blair HF, Williams RP, et al. Grading liposarcomas with PET using [18F]FDG. J Comput Assist Tomogr 1990;14(6):960–962. 15. Ioannidis JP, Lau J. 18F-FDG PET for the diagnosis and grading of softtissue sarcoma: a meta-analysis. J Nucl Med 2003;44(5):717–724. 16. Nieweg OE, Pruim J, van Ginkel RJ, et al. Fluorine-18-fluorodeoxyglucose PET imaging of soft-tissue sarcoma. J Nucl Med 1996;37(2):257–261. 17. Bastiaannet E, Groen H, Jager PL, et al. The value of FDG-PET in the detection, grading and response to therapy of soft tissue and bone sarcomas; a systematic review and meta-analysis. Cancer Treat Rev 2004;30(1): 83–101.

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17 Other Tumors Jian Qin Yu and Martin Charron

Positron emission tomography (PET) is a new and powerful imaging tool that has been successfully employed to diagnose many adult tumors. Incidental tumor detection by PET has been reported (1–5), as well as detection of chronic cholecystitis, aspiration pneumonia, and other benign conditions (6–8). The implementation of this new technology has been slower in the pediatric population than in the adult population. PET has shown promise in a variety of pediatric tumors such as those of the central nervous system, lymphomas, neuroblastoma, bone, and soft tissue tumors; these are discussed in other chapters. Positron emission tomography evaluations for diagnosis and therapy in the pediatric population were reported in the early and mid-1980s (9–11). The early studies focused on brain tumors, metastatic tumors to the brain, and metabolic abnormalities such as Sturge-Weber syndrome (12). Many of the studies in the 1990s also focused on brain tumor. This chapter discusses other rare tumors not covered in other parts of this book.

Ewing’s Sarcoma There are few reports regarding PET with Ewing’s sarcoma. One early scientific report in a pediatric population was by Shulkin et al. (13) from the University of Michigan Medical Center in the mid-1990s, in which the author showed that PET is superior to bone scan in detecting bone metastasis in a patient with Ewing’s sarcoma. A case report later demonstrated that PET is superior to both bone scan and gallium, especially when the disease involves the bone marrow (14). Another study comparing PET and magnetic resonance imaging (MRI) for detection of Ewing’s metastasis concluded that PET is more sensitive (15). The findings reinforced the uses of a functional imaging modality, such as PET, over anatomic imaging. A large amount of clinical research has assessed the role of PET in evaluating the response to chemotherapy. Fluorodeoxyglucose (FDG)PET standard uptake values (SUVs), or tumor-to-nontumor ratio 312

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(T/NT) before and after chemotherapy, were analyzed and correlated with the chemotherapy response assessed by histopathology in surgically excised tumors. Good response correlated with relatively benign histology and had markedly decreased SUV or T/NT on posttherapy scans (16,17). Two reviews by Franzius et al. (17,18) found that for the detection of osseous metastases of Ewing’s sarcoma, therapy monitoring, and the diagnosis of recurrences, FDG-PET was useful. This conclusion is echoed by a recent paper by McCarville et al. (19) that stated that PET is useful in monitoring response to different therapies and aids the postoperative evaluation of tumor resection sites.

Neurofibromatosis Type 1 Neurofibromatosis type 1 (NF1) is an autosomal-dominant genetic disorder commonly associated with neuropsychological complications. Focal areas of high signal intensity on magnetic resonance imaging (MRI) scans occur commonly. However, there is inconsistent correlation with neuropsychological problems. Biopsy may be the gold standard for a definitive answer, but it is invasive, unpleasant, and prone to sampling errors. Kaplan et al. (20) reported the findings of PET scans utilizing FD6 and MRI studies on 10 children with NF1. This study focused on multiple focal areas of high signal intensity to evaluate the regional cerebral metabolic rate for glucose in these lesions and other central nervous system structures. Visual inspection and semiquantitative analysis of PET images demonstrated thalamic hypometabolism and varying degrees of cortical inhomogeneity in all cases of NF1 compared to normal controls. The metabolic abnormalities noted in this study suggest a potential relationship between these structures and the neuropsychological dysfunctions noted in NF1. We recently reported our experience in 28 patients (16 males, 12 females) with an age range from 4 years to 35 years (21,22). Twentysix were clinically stable, but were considered high risk for progression, based on the anatomic location or the change in the size of the lesion over time. All patients enrolled from Children’s Hospital of Philadelphia (CHOP) had undergone MRI studies as part of standard patient care. FD6 PET scans were obtained for baseline assessment of the disease activity within 2 weeks of the first MRI study. Positron emission tomography images were performed with a dedicated PET camera following a standard protocol. The images were interpreted with and without attenuation correction. Correlation was made to MRI on a lesion-by-lesion basis whenever possible. Standard uptake value was determined for all identifiable lesions on PET scan. The common sites of involvement by plexiform neurofibromas were the face, neck, trunk, and extremities. Twenty-three of 28 patients (82%) showed various degrees of FDG uptake as focal abnormalities. The number of lesions ranged from one to over 10 per patient. The location of FDG-PET abnormalities in these patients corresponded to those noted on the MRI scans. The SUV was calculated for all identifiable lesions on PET, and their

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values ranged from 1.0 to 5.3. Most lesions had a low SUV, which further corroborates the benign nature of these lesions. Five of 28 patients (18%) did not show any identifiable abnormal focal uptake. Now MRI is used as the gold standard to determine progression of the lesions. Our findings agree with those of Ferner et al. (23,24), who reported an SUV range of 0.56 to 3.3 for benign plexiform neurofibromas

Pheochromocytoma The first report evaluating PET in pheochromocytoma was by Shulkin’s group (25) using C-11 hydroxyephedrine (HED); they reported excellent imaging quality superior to that obtained from planar and tomographic meta-iodobenzylguanidine (mIBG) studies. A recent study confirmed the accuracy of the C-11 HED (26). However, its clinical availability is limited by the tracer C-11, which needs an on-site cyclotron, which is not generally available for most daily clinical practice. Another early study suggested using iodine-124 mIBG probes (27), which also faces the problem of tracer availability. Several later studies evaluated FDG-PET scanning for the detection of pheochromocytoma (28). Shulkin et al. (29) demonstrated that most pheochromocytomas accumulate FDG to a greater percentage in malignant versus benign pheochromocytoma. Fluorodeoxyglucose-PET is especially useful in defining the distribution of those pheochromocytoma that fail to concentrate mIBG (29). A PET scan with both FDG and rubidium 82 has been reported to be successful (30). Carbon-11 metomidate (31) was evaluated for its ability to discriminate lesions of adrenal cortical origin from noncortical lesions. However, a favored tracer is 6-18F-fluorodopamine, which has been shown to detect pheochromocytoma with high sensitivity in patients with known disease (32–34). In those reports PET is much more sensitive than iodine-131 mIBG (35). One German study reported results with 18F-DOPA (36). To discriminate between benign and malignant lesions, FDG is the tracer of choice (37). Because pheochromocytomas are potentially curable with surgery, the diagnosis and exact localization are very important. The recent imaging recommendations are anatomic imaging followed by mIBG scintigraphy. A negative mIBG study should be followed by an FDOPA study, which is more specific (38–42).

Other Neuroendocrine Tumors Neuroendocrine tumors were evaluated with FDG-PET with variable success. Scintigraphy with mIBG and octreotide are still the studies of choice. However, in our experience PET scan showed some potential clinical application. We evaluated whether FDG-PET can be successfully utilized in the evaluation of tumors that are commonly examined by Octreoscan; we retrospectively reviewed 34 FDG-PET scans performed from 1998 to 2002 to evaluate recurrent or metastatic tumors

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that were considered optimal candidates for Octreoscan (43). Among these, 25 patients were noted to have complete follow-up and therefore were included for final analysis; five had carcinoid, seven had islet cell tumors, five had pheochromocytoma, seven had medullary carcinoma of the thyroid, and one had Cushing’s syndrome. Thirteen of these patients also had concurrent ostreoscan. Final diagnosis was made based on surgical findings, clinical follow-up, and results of other imaging modalities. Fluorodeoxyglucose-PET detected 16 of 17 patients who were proven to have recurrent or metastatic disease, with a sensitivity of 94.1%. It excluded seven of eight patients proven not to have recurrent or metastatic disease—a specificity of 87.5%. Among 13 patients with both FDG-PET and Octreoscan in whom eight patients were proven to have disease, FDG-PET correctly detected seven whereas Octreoscan detected five. On the other hand, five patients with negative results on both tests proved to be disease-free. One patient had islet cell tumor that was detected by neither FDG-PET nor Octreoscan. Fluorodeoxyglucose-PET excluded four of five patients with one false-positive result (inflammation), whereas Octreoscan excluded five of five patients. Thus our data indicate that FDG-PET and Octreoscan provide comparable results in patients who are considered optimal candidates for Octreoscan, although FDG-PET is slightly more sensitive whereas Octreoscan appears to be slightly more specific. Considering the similar cost of these two examinations, FDG-PET may prove to be more efficient in this setting because of its substantially superior image quality (whole body vs. regional tomographic images) and convenience to the patient (2 hours vs. 24 hours for completion of the test). There is little in the current literature to document the utility of PET in pediatric endocrine tumors (44,45). A recent article suggests that 18Ffluoro-L-DOPA could be an accurate noninvasive technique to distinguish between focal and diffuse forms of hyperinsulinism (46).

Liver Tumors Primary liver tumors’ uptake of FDG showed good correlation with the patient’s a-fetoprotein (AFP) (47). Another series from Germany demonstrates that PET is better than computed tomography (CT) and ultrasonography, but not MRI (48). The greatest value of PET scan appears to be in the detection of extrahepatic tumor, which is a very useful addition to the currently used anatomically based images in all cases of advanced tumor.

Germ Cell Tumors Fluorodeoxyglucose-PET scan has been used in the detection and management of different germ cell tumors since 1995 (49–51). Posttherapy studies employed PET soon afterward (52–55). A pilot study in 2000 tested the utility of PDG-PET in the initial staging of the germ

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cell tumors (56). The sample size is small (31 patients), and a large prospective study is needed. A later study failed to find a benefit of FDG-PET over CT (57). However, it confirmed the value of PET in restaging patients. Positron emission tomography appears to be less sensitive to detect small retroperitoneal nodes (58). L-[1–11C] tyrosine was found to be insufficiently sensitive for clinical use (59).

Histiocytosis X Studies evaluating histiocytosis were recent (8,60–67), and most of them were case reports (8,64–67). There are no large-scale studies with sufficient patient sample size. Anatomic imaging remains the favored modality. Positron emission tomography may provide additional information for evaluation of distant sites.

Retinoblastoma Currently, there is only one report of FDG-PET being used to detect retinoblastoma (68). This study did not support the use of FDG-PET, as the PET findings did not correlate with clinical or histopathologic features. Further study with more patients will be of value.

Conclusion Fluorodeoxyglucose remains the most frequently used tracer. New tracers for different conditions are currently being evaluated worldwide. Positron emission tomography remains poorly evaluated in the pediatric population (69). The recent merger of the Children’s Cancer Group and the Pediatric Oncology Group to form the Children’s Oncology Group creates an opportunity to examine the use of FDG-PET in the management of childhood tumors in multiinstitutional, cooperative efforts (70).

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hydroxylase tracer (11)C-metomidate. Eur J Nucl Med Mol Imaging 2004; 31:1224–1230. Lenz T, Gossmann J, Schulte KL, Salewski L, Geiger H. Diagnosis of pheochromocytoma. Clin Lab 2002;48:5–18. Ilias I, Pacak K. Anatomical and functional imaging of metastatic pheochromocytoma. Ann N Y Acad Sci 2004;1018:495–504. Maurea S, Caraco C, Klain M, Mainolfi C, Salvatore M. Imaging characterization of non-hypersecreting adrenal masses. Comparison between MR and radionuclide techniques. Q J Nucl Med Mol Imaging 2004;48: 188–197. Brink I, Hoegerle S, Klisch J, Bley TA. Imaging of pheochromocytoma and paraganglioma. Fam Cancer 2005;4:61–68. Minn H, Salonen A, Friberg J, et al. Imaging of adrenal incidentalomas with PET using (11)C-metomidate and (18)F-FDG. J Nucl Med 2004;45: 972–979. Zhuang H, Yu J, Dadparvar S, et al. Accuracy of FDG-PET in the evaluation of metastatic or recurrent tumors which are candidates for Octreoscan (abstract). J Nucl Med 2003;44:73. Sasi OA, Sathiapalan R, Rifai A, et al. Colonic neuroendocrine carcinoma in a child. Pediatr Radiol 2005;35:339–343. Scanga DR, Martin WH, Delbeke D. Value of FDG PET imaging in the management of patients with thyroid, neuroendocrine, and neural crest tumors. Clin Nucl Med 2004;29:86–90. Ribeiro MJ, De Lonlay P, Delzescaux T, et al. Characterization of hyperinsulinism in infancy assessed with PET and 18F-fluoro-L-DOPA. J Nucl Med 2005;46:560–566. Shang JB, Li YH, Liu FY, et al. [18F-Fluorodeoxyglucose uptake in hepatocellular carcinoma on positron emission tomography correlates with alphafetoprotein]. Di Yi Jun Yi Da Xue Xue Bao 2004;24:697–699. Bohm B, Voth M, Geoghegan J, et al. Impact of positron emission tomography on strategy in liver resection for primary and secondary liver tumors. J Cancer Res Clin Oncol 2004;130:266–272. Wilson CB, Young HE, Ott RJ, et al. Imaging metastatic testicular germ cell tumours with 18FDG positron emission tomography: prospects for detection and management. Eur J Nucl Med 1995;22:508–513. Okamura T, Kawabe J, Kobashi T, et al. [A case of peritoneal metastasis from retroperitoneal yolk sac tumor diagnosed by 67Ga-scan and 18F-FDGPET]. Kaku Igaku 1995;32:495–499. Bachor R, Kocher F, Gropengiesser F, Reske SN, Hautmann RE. [Positron emission tomography. Introduction of a new procedure in diagnosis of urologic tumors and initial clinical results]. Urologe A 1995;34:138–142. Cremerius U, Effert PJ, Adam G, et al. FDG PET for detection and therapy control of metastatic germ cell tumor. J Nucl Med 1998;39:815–822. Nuutinen JM, Leskinen S, Elomaa I, et al. Detection of residual tumours in postchemotherapy testicular cancer by FDG-PET. Eur J Cancer 1997;33: 1234–1241. Hartmann JT, Schmoll HJ, Kuczyk MA, Candelaria M, Bokemeyer C. Postchemotherapy resections of residual masses from metastatic nonseminomatous testicular germ cell tumors. Ann Oncol 1997;8:531–538. Stephens AW, Gonin R, Hutchins GD, Einhorn LH. Positron emission tomography evaluation of residual radiographic abnormalities in postchemotherapy germ cell tumor patients. J Clin Oncol 1996;14: 1637–1641.

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Chapter 17 Other Tumors 56. Hain SF, O’Doherty MJ, Timothy AR, Leslie MD, Partridge SE, Huddart RA. Fluorodeoxyglucose PET in the initial staging of germ cell tumours. Eur J Nucl Med 2000;27:590–594. 57. Spermon JR, De Geus-Oei LF, Kiemeney LA, Witjes JA, Oyen WJ. The role of (18)fluoro-2–deoxyglucose positron emission tomography in initial staging and re-staging after chemotherapy for testicular germ cell tumours. BJU Int 2002;89:549–556. 58. Cremerius U, Wildberger JE, Borchers H, et al. Does positron emission tomography using 18–fluoro-2–deoxyglucose improve clinical staging of testicular cancer?—results of a study in 50 patients. Urology 1999;54: 900–904. 59. Kole AC, Hoekstra HJ, Sleijfer DT, Nieweg OE, Schraffordt Koops H, Vaalburg W. L-[1–carbon-11]tyrosine imaging of metastatic testicular nonseminoma germ-cell tumors. J Nucl Med 1998;39:1027–1029. 60. Steiner M, Prayer D, Asenbaum S, et al. Modern imaging methods for the assessment of Langerhans’ cell histiocytosis-associated neurodegenerative syndrome: case report. J Child Neurol 2005;20:253–257. 61. Buchler T, Cervinek L, Belohlavek O, et al. Langerhans cell histiocytosis with central nervous system involvement: follow-up by FDG-PET during treatment with cladribine. Pediatr Blood Cancer 2005;44:286–288. 62. Hoshino A, Kawada E, Ukita T, et al. Usefulness of FDG-PET to diagnose intravascular lymphomatosis presenting as fever of unknown origin. Am J Hematol 2004;76:236–239. 63. Binkovitz LA, Olshefski RS, Adler BH. Coincidence FDG-PET in the evaluation of Langerhans’ cell histiocytosis: preliminary findings. Pediatr Radiol 2003;33:598–602. 64. Blum R, Seymour JF, Hicks RJ. Role of 18FDG-positron emission tomography scanning in the management of histiocytosis. Leuk Lymphoma 2002;43:2155–2157. 65. Menzel C, Hamscho N, Dobert N, et al. PET imaging of Rosai-Dorfman disease: correlation with histopathology and ex-vivo beta-imaging. Arch Dermatol Res 2003;295:280–283. 66. Lim R, Wittram C, Ferry JA, Shepard JA. FDG PET of Rosai-Dorfman disease of the thymus. AJR 2004;182:514. 67. Pereira Neto CC, Roman C, Johnson M, Jagasia M, Martin WH, Delbeke D. Positron emission tomography/computed tomography of a rare xanthogranulomatous process: Erdheim-Chester disease. Mol Imaging Biol 2004;6:63–67. 68. Moll AC, Hoekstra OS, Imhof SM, et al. Fluorine-18 fluorodeoxyglucose positron emission tomography (PET) to detect vital retinoblastoma in the eye: preliminary experience. Ophthalmic Genet 2004;25:31–35. 69. Connolly LP, Drubach LA, Ted Treves S. Applications of nuclear medicine in pediatric oncology. Clin Nucl Med 2002;27:117–125. 70. Jadvar H, Alavi A, Mavi A, Shulkin BL. PET in pediatric diseases. Radiol Clin North Am 2005;43:135–152.

Section 3 Neurology and Psychiatry

18 The Developing Brain Lorcan A. O’Tuama and Paul R. Jolles

This chapter reviews the development of the normal brain primarily as studied with nuclear imaging methods, with an emphasis on radiopharmaceutical-based methods [positron emission tomography (PET), single photon emission computed tomography (SPECT), and PET— computed tomography (PET-CT)]. These methods retain unchallenged specificity and sensitivity for certain important neurochemical events. We will also cover advances in allied techniques, including magnetic resonance imaging (MRI)-based and electrophysiologic methods. The functional modalities of PET and SPECT are best studied concurrently with structural modalities, including MRI and CT. In selected cases, both functional MRI (fMRI) and nonimaging modalities such as magnetic resonance spectroscopy (MRS) allow for in vivo molecular speciation, and can be brought to bear as well as magnetoencephalography (MEG). The recent introduction of hybrid PET-CT methods introduces a further dimension by allowing direct comparison of functional and structural features in a fused data set. By including these intermodality comparisons we hope to provide a more integrated and mutually explanatory exposition of the imaging of normal brain development.

Brain Imaging Studies Anatomic Studies of Normal Brain Development It is essential to discuss the basic structural framework before going on to the more functional insights of MRI. In an early study, Barkovich et al. (1) used 1.5-tesla MRI with the classic spin-echo sequences (T1, T2) to examine 82 neurologically normal-appearing infants, and gave a useful review of the time course of attainment of the major structural developmental milestones. The authors found by these imaging criteria that brain maturation commenced in the brainstem and spread centrifugally to the cerebellum and supratentorial levels. T1-weighted images were most sensitive for assessment of normal brain development in the first 6 to 8 months of life, and T2-weighted images were most sensitive thereafter. 323

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Radiopharmaceutical-Based Studies of Normal Brain Development Advances in radiolabeling have resulted in the development of a large number of radiopharmaceuticals utilized to evaluate metabolism, blood flow and perfusion, neuroreceptor occupancy, genetic targets, and a host of other biochemical processes. These include both gammaemitting and positron-emitting tracers. As applied to brain imaging, markers of cerebral glucose and amino acid metabolism [in particular, fluorine-18 (18F)-2-fluorodeoxyglucose (FDG) and carbon-11 (11C)l-methionine, respectively] and cerebral blood flow/perfusion [oxygen-15 (15O)-CO2, 15O-water, xenon 133 (133Xe), iodine-123 (123I)iodoamphetamine, technetium-99m (99mTc)-bicisate and 99mTcexametazime] have been employed most often. SPECT Study of Normal Developmental Changes in Cerebral Blood Flow Rubinstein et al. (2), using 123I-iodomethylamphetamine (123I-IMP) SPECT, assessed normal evolution of regional cerebral blood flow (rCBF) as a function of age. Thirty babies with normal clinical examination were retrospectively studied. Perfusion in thalamic structures exceeded that of the cortex until the end of the second month. Within the supratentorial brain, the parietal and occipital areas initially visualized about the 40th week and rose rapidly in the postnatal period. Frontal activity was clearly detectible only by the second month and rose markedly to reach adult levels by the second year. The authors felt rCBF changes paralleled achievement of early behavioral milestones. Thus the early emphasis on brainstem perfusion partly paralleled the morphologic developmental sequence reported by Barkovich et al. (1). Chiron et al. (3) examined rCBF with 133Xe-SPECT in 42 infants and children (ages 2 days to 19 years) considered developmentally normal. Regions of interest (ROIs) were placed to depict the cortical regions, cerebellum, and thalamus. At birth, cortical rCBFs were lower than those for adults; after birth they increased up to 6 years of age to values 50% to 85% higher than in adults and thereafter decreased, reaching adult levels at between 15 and 19 years of age. Neonatal values of rCBF in cerebellum and thalamus were slightly higher than adult levels, but not significantly; after age 1, they followed the common pattern for cortical curves. The time needed to reach normal adult values differed for each cortical region. The shortest time was found for the primary sensorimotor cortex and the longest for the visual associative cortex. This work provided an important clinical rationale for pursuing brain perfusion SPECT studies in that cognitive development of the child seemed to be related to changes in blood flow of the corresponding brain regions. The study hinted at another interesting aspect of brain development, suggesting an initial period of “overperfusion” or “luxury” perfusion. These changes somewhat paralleled PET studies, as discussed below, which also provide evidence for an initial hypermetabolic period in the immature brain, with overperfusion followed by a drop to typical adult values.

L.A. O’Tuama and P.R. Jolles

PET Studies of Metabolic Brain Development Positron emission tomography has become an indispensable imaging tool in clinical nuclear medicine (4). Especially in combination with CT (now optimized by the direct simultaneous acquisition feasible with PET-CT) and MRI, PET is an established method with wide application in neurology, cardiology, infectiology, and oncology. Compared with its widespread application in adults, however, clinical use of PET in pediatrics is still relatively limited. Possible reasons include the small number of clinical and prospective studies of PET obtained for pediatric as compared with adult imaging indications. Furthermore, only a limited number of PET scanners are available for pediatric imaging. Generally recognized current important indications for pediatric PET include diagnosis and follow-up assessment of Hodgkin’s and nonHodgkin’s lymphoma and primary brain tumors, and in defining the seizure focus site for epileptic seizures. Positron emission tomography study of normal brain development has been less emphasized but is of potentially far-reaching importance. Studies using functional imaging techniques such as PET scans have shown a pattern of metabolic activity that varies in different regions of the brain at different ages. Fluorodeoxyglucose Studies Unless under conditions of starvation (in which ketones are available), the brain utilizes glucose as an energy substrate (5). The most commonly utilized marker of glucose metabolism is FDG, a tracer method that evolved from Sokoloff et al.’s (6) original work involving autoradiography and the localization of 14C-2-deoxyglucose in the rat substrate. Although earlier investigations of cerebral circulation and metabolism in children were also conducted (7), the ability to image and quantify vivo metabolic processes was significantly advanced after the development and evolution of modern PET instrumentation (8). In a classic study, Chugani et al. (9) studied 29 infants and children (ages 5 days to 15.1 years) who had suffered transient neurologic events not significantly affecting normal neurodevelopment. In infants less than 5 weeks old, the local cerebral metabolic rate of glucose (lCMRGl) utilization, a PET parameter, was highest in sensorimotor cortex, thalamus, brainstem, and cerebellar vermis. In cortex, lCMRGl increased first in divisions of occipital cortex and by 2 years had reached essentially adult values in all or most regions. Between 6 months and a year, metabolic activity was marked in the frontal cortex, paralleling development clinically of higher cortical functions, including individual interpersonal interactions, stranger anxiety, and other behaviors. Rates of up to 65 mmol/min/100 g were reached in most regions and persisted until about 9 years. Thereafter, a progressive decline set in, with adult values being reached around 20 years of age. The time course of this metabolic time profile paralleled the phases of production and regression of neurons, synapses, and dendritic spines, as established from morphologic studies. The detailing of this sequence was reasonably postulated as a prerequisite to study of the brain metabolic response in diverse encephalopathies. This sequence of imaging-

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defined functional events may underlie and provide the biologic basis for the clinically observed critical period of learning and emotional development. More recently, the effect of brain development on cerebral glucose metabolism was evaluated in 20 neurodevelopmentally normal infants (postconceptional age: 32.7 to 60.3 weeks) (10). It was reported that the lCMRGl in various cortical regions and in the basal ganglia was low at birth (from 4 to 16 mmol/min/100 g). Infants 2 months of age and younger showed the highest lCMRGl in the sensorimotor cortex, thalamus, and brainstem. At 5 months, there was an increase in the lCMRGl in the frontal, parietal, temporal, occipital, and cerebellar cortical regions. Generally, the whole brain lCMRGl correlated with postconceptional age, and the change in the glucose metabolic pattern reflected functional maturation of these regions. Based on these data, it seems that regional glucose metabolism is a credible marker of brain maturation. The effect of neonatal hypoglycemia on cerebral glucose metabolism was studied in a small group of eight infants (11). The infants were studied with FDG-PET at ages 5.3 ± 6.2 days during normoglycemia and compared to the age-adjusted lCMRGl of eight infants with suspected hypoxic-ischemic brain injury but with normal neurologic development. After neonatal hypoglycemia, the whole brain ageadjusted lCMRGl was not lower than that of the control group and seemed to be normal. Although the ability to quantify regional cerebral metabolic rates is highly desirable, techniques less invasive than arterial blood sampling have been proposed for early infancy (12). Using a Patlak analysis, the input function was derived by using a combined time-activity curve (derived from left ventricular activity and venous whole blood activity concentration) and by using the activity concentration in whole blood venous samples. These methods showed good correlation, as did an alternative method using standard uptake values (SUV) correlated to lCMRGl values. It appears that reasonable estimations of lCMRGl can be obtained with techniques other than arterial sampling. Labeled Amino Acid PET Studies O’Tuama used a dual-probe positron detection system and also retrospective data fit on normal-appearing brain regions of 11C-Lmethionine PET to study age-associated changes in amino acid transport from blood to normal frontal cortex (13). Seventeen patients, 1.8 to 71 years of age, were studied. Each patient received two scans in an attempt to assess competitive inhibition of 11C-L-methionine uptake. The first study was performed using tracer doses of the radiopharmaceutical only. One hour before a second PET study, each subject received either oral L-phenylalanine or an intravenous infusion of amino acids, as competing substrates for the neutral amino acid transport system. Uptake of 11C-L-methionine by frontal cortex decreased sevenfold between 1.8 and 71 years of age (r = -0.71; p < .05). Concomitantly measured blood-to-brain transfer of 11C-L-methionine, at 4.5 years, exceeded mean adult values by more than fivefold. Competitive inhibition reduced L-methionine uptake in all patients older than 4.6 years. These developmental changes parallel findings in animals.

L.A. O’Tuama and P.R. Jolles

The results of Chugani et al. (9) and O’Tuama, as pointed out by Robinson et al. (14), suggest a significant age-dependence for two different neurometabolic systems—the overall rate of glycolysis and glucose cell membrane transport (FDG), versus amino acid transport and protein synthesis (methionine). PET Radiation Exposure A concern intrinsic to the medical and research use of PET radiopharmaceuticals is whether the radiation dose to the newborn or young child is acceptable. Based on the medical internal radiation dose (MIRD) model, the radiation dose to newborn children from FDG has been estimated and has been found to differ from that noted in adults. The radioactivity concentration in the brain and urinary bladder was measured to determine accumulated activity in 21 infant FDG studies. A greater proportion of the tracer was noted to accumulate in the brain of infants than in adults (9% versus 7%, respectively, perhaps partly due to relatively greater brain mass), and less was excreted into the urine (7% versus 20%, respectively). However, there was a large individual variation in the latter. Overall, the dose to the bladder wall was less than for adults, and the greater amount of radioactivity remaining in the body of infants may increase the dose to other organs. Although the calculations were based on upper estimates, the estimated radiation dose from FDG studies was lower in infants compared to adults. Infant FDG studies also had a lower calculated radiation dose compared to conventional nuclear medicine studies such as 99mTcmethylene diphosphonate bone scintigraphy.

Correlation of SPECT with Other Modalities: MR Imaging and MRS Tokumaru et al. (15) noted that the precise relationship between function and anatomic brain maturation remains unclear. They studied the changes of rCBF in 42 infants and children, ages 2 days to 19 years, using 123I-IMP-SPECT correlated with MR findings and known developmental changes. The subjects suffered transient neonatal neurologic events, without an overt effect on subsequent neurodevelopment. Beginning at the 34th postconceptional week, there was predominant uptake in the thalami, brainstem, and paleocerebellum, with less cortical activity. Subsequent evolution of rCBF showed a similar regional pattern to the studies of Rubinstein et al. (2) and Chiron et al. (3), and a general parallel to the values for lCMRGl as established by Chugani et al. (9). Also, these changes paralleled T1 and T2 standard spin-echo MRI, and were consequently attributed presumptively to the major neurodevelopmental event of myelination. Minor limitations in the study include lack of specific inversion recovery MR pulse sequences for characterization of myelin development, and the spatial limitations of region definition with 123I-IMP-SPECT. Interesting speculations from these results included the idea that metabolic demands associated with myelination may “drive” the rCBF pattern in the developing brain. At the practical level, it was pointed out that awareness of evolving normal MRI and PET or SPECT patterns during development is crucial

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Figure 18.1. Patient at about 34 weeks’ gestational age. Axial (A), coronal (B), and sagittal (C) SPECT scans show prominent cerebral perfusion in thalami, brainstem, and cerebellum. There was low activity in the paracentral gyri area.

for interpretation of pediatric studies. Thus the time course of the changes in 123I-IMP uptake in the developing brain as detected by SPECT is similar to that of myelination and most likely reflects an overall topologic maturational pattern of the brain (Fig. 18.1). Ogawa et al. (16) obtained similar results. Subsequently, newer imaging methods and pulse sequences have been applied to extend our knowledge of the physiology of the developing brain. Zhang et al. (17) used diffusion-weighted sequences, with fitting of data to a triple-gaussian model, to show that brain diffusion decreases and brain volume increases during maturation. They focused on regions showing a range of gray and white matter composition. Filippi et al. (18) showed changes in diffusion constant and anisotropy in infants with developmental delay despite a normal appearance with conventional MRI techniques. These results further illustrate the potential importance of techniques beyond conventional structural MRI for objective assessment of neurodevelopment. Other parameters of normal brain development that can be approached by imaging methods include changes in brain water diffusion as studied by diffusion-tensor MRI (18). This study had 167 participants, ages 31 gestational weeks to 11 postnatal years. An isotropic diffusion model was applied to the gray matter of the basal ganglia and thalamus. Maturational decreases of the diffusion tensor eigenvalues were consistent with models reflecting influence of brain water content and myelination. Magnetic resonance spectroscopy represents another noninvasive method for the study of normal brain development (19). In a review

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article, Hedlund (20) illustrated how normal white matter spectra with identification of critical neurometabolites can be achieved in children as young as 2 years. These neurometabolites include compounds such as N-acetylaspartate (NAA), a primarily neuronal marker as well as choline, a marker of turnover of myelin and other important cell membranes. Abnormal metabolites such as lactate are undetectable in the normal spectra and are readily revealed in encephalopathies. The studies have relatively short acquisition times, are noninvasive, and thus are feasible even in young sedated patients. More recently, the technique of dynamic susceptibility contrastenhanced (DSCE) MRI technique has been used to measure rCBF in newborns (21). This method requires a first-pass contrast bolus, which presents a formidable limitation in neonates and infants, as does the problem of artifacts resulting from bulkhead motion. However, images of perfusion were calculated in 12 of 27 subjects. Major vascular structures such as the circle of Willis could be identified. Values of rCBF were generally larger in gray matter than in white matter. Attempts have been made to obtain three-dimensional (3D) MRS to study the anatomic distributions of choline, creatine, and NAA in a small group of premature and term infants (22). The basic feasibility of such studies was demonstrated. The results showed topologic and age-dependent variations in the white matter regions of the premature infants. However, there is concern about small sample size and lower signal-to-noise ratio. There is need for substantial further effort to establish an adequate normal database for this age group. The notion of human brain plasticity is an important concept developed in part from developmental imaging studies of the kind just reviewed. For example, Chugani (23) discussed correlations between lCMRGl and synaptogenesis and has advocated that the PET findings have important implications with respect to potential recovery of regional brain functions following injury and for the concept of “critical periods” for learning capacity. Indirect support for the existence of normal brain functional plasticity has been inferred from studies of abnormal conditions. Thus Helmstaedter and Elger (24), studying patients undergoing left anterior temporal lobectomy, showed varying regional effects on parenchymal plasticity depending on extent of damage and the specific neocortical function involved.

Pediatric PET-CT Brain Imaging The advent of PET-CT offers further opportunity to delineate these events with increased spatial accuracy with the use of both intermodality fused data sets, as well as high-resolution positron imaging. In normal subjects, uniformly high metabolic uptake in the brain, particularly in brain parenchymal gray matter (GM) structures such as basal ganglia, thalamus, and cerebellum, has limited its use for lesion detection, as discussed elsewhere. However, this feature is a boon for evaluation of normal metabolic variants. The technique involves coupling of PET and CT scanning into a hybrid system. This allows both studies to be done together in what is now known as a PET-CT scanner. The CT acquisition,

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designed (in many centers) so as not to be diagnostic, but rather to provide adequate attenuation correction and resolution for co-registration, is performed with approximately 2 to 4.25 mm thick contiguous slices, 100 mAs, 140 kVp. The PET phase of the study is performed with 5- to 10-minute acquisition per imaging level. These systems have the outstanding advantage for pediatric sets of minimizing study times. One platform combines a high resolution and ultrafast multislice CT system with PET optimized for routine 2D and 3D acquisitions. The attached software facilitates postprocessing stages and allows interactive analysis of both data sets. Ionic oral contrast (often administered 1 hour prior to imaging to opacify the bowel for whole-body applications) is omitted. A dose of 18F-FDG, titrated by weight and standard conversion factor, is given intravenously 1 hour prior to imaging, and the patient voids prior to imaging to decrease bladder activity (25). The older, cooperative child is positioned supine on the imaging table, with the head comfortably positioned in a cushioned head holder and arms at the patient’s side. Following tracer injection, it is useful to have the patient rest in a quiet environment, instructed to limit verbal and physical activity during the major tracer uptake phase (about 20 minutes). A qualitative analysis is the most common method for pediatric brain PET-CT and, with an experienced observer, is usually adequate. Typically, a workstation review is made of all orthogonal images with varying gray scale and color image presentation, rotating views, and maximum intensity projection images (Fig. 18.2). A

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Figure 18.2. A–C: SPECT scans show almost similar appearance to adult pattern. D,E: Axial spin echo (600/15) MR images show myelination in frontal and temporal areas. [Source: Tokumaru et al., (14) with permission.]

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Conclusion Techniques used for mapping of brain function are usefully reviewed by Santosh (26). Brain morphology and tissue composition will continue to be elucidated mainly with MRI and CT. Information on neuronal activity and communication will continue to be provided at the electromagnetic (EEG, MEG) level. Biochemical aspects of neurotransmission will be studied by general mapping of blood flow and tissue metabolism with standard PET and SPECT methods, supplemented by tissue typing using MRS. Energy-dependent metabolic processes will be assessed most specifically with selective PET ligand and metabolite radiopharmaceuticals. Clinically relevant neurotransmitters and receptors include D1 antagonists in prefrontal cortex, hippocampus, and amygdala; D2 receptor agonist, which localizes mainly in the striatum; and 5-hydroxytryptamine (5HT)1A, 5HT2A, and 5HTa2 receptor ligands. Also, ligands that help quantify receptors such as N-methyl-D-aspartate (NMDA), a-amino-3-hydroxy-5-methyl-4isoxazolepropionate (AMPA), etc., will help understanding both of normal function of these systems, and of their specific abnormalities in the neurodevelopmental disorders. Functional MRI will assist these efforts, mainly by measuring activation-associated changes in brain perfusion. Advances in MR technique will contribute significantly. These will include rapid MR scanning (gradient echo, fast spin echo, and planar sequences), contrast-based fMRI techniques, diffusion MRI, arterial spine labeling (ASL), and dynamic susceptibility MR perfusion imaging of the brain. Other important anticipated improvements in technology will relate to reduction of movement artifacts, imaging data reduction, and postimaging data processing. Among these exciting future developments, nuclear medicine technology is likely to continue to play a unique and unchallenged role. Radiopharmaceutically based imaging technology retains the highest sensitivity of available modalities (including MRI, fMRI, MRS, EEG, and MEG) for depiction of biochemical processes occurring in the picomolar to nanomolar range. This specificity extends to presynaptic neurotransmitter molecules, which can be separated from receptor systems that are mainly postsynaptic, only 20 to 50 nM apart. Therefore, nuclear techniques will play an increasingly important and visible role as developmental mapping of neurotransmitters and synaptic systems comes to the fore. Correlation with the more spatially detailed modalities reviewed here will be important in gleaning the ultimate information from such studies. In this regard, ultimately the use of combined functional and structural data sets as pioneered with PETCT systems will provide the method of choice. Studies on normal children, within ethical limits, will continue to give important and critical new insights into the neurofunctional underpinnings of normal childhood cognitive and emotional processes.

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References 1. Barkovich AJ, Kjos BO, Jackson DE Jr, Norman D. Normal maturation of the neonatal and infant brain: MR imaging at 1.5 T. Radiology 1988; 166(1 pt 1):173–180. 2. Rubinstein M, Denays R, Ham HR, et al. Functional imaging of brain maturation in humans using iodine-123 iodoamphetamine and SPECT. J Nucl Med 1989;30(12):1982–1985. 3. Chiron C, Raynaud C, Maziere B, et al. Changes in regional cerebral blood flow during brain maturation in children and adolescents. J Nucl Med 1992;33(5):696–703. 4. Hahn K, Pflunger T. Has PET become an important clinical tool in the paediatric imaging? Eur J Nucl Med Mol Imaging 2004;31(5):615–621. 5. Sokoloff L, Relationships among local functional activity, energy metabolism, and blood flow in the central nervous system. Fed Proc 1981;40(8): 2311–2316. 6. Sokoloff L, Revich M, Kennedy C, et al. The [14C]deoxyglucose method for the measurement of local cerebral glucose utilization: theory, procedure, and normal values in the conscious and anesthetized albino rat. J Neurochem 1977;28:897–916. 7. Kennedy C, Sokoloff L, Anderson W, Duffy P. Studies in cerebral circulation and metabolism in children. Trans Am Neurol Assoc 1954;13:196–198. 8. Phelps ME, Huang SC, Hoffman EJ, Selin C, Sokoloff L, Kuhl DE. Tomographic measurement of local cerebral glucose metabolic rate in humans with (F-18)2–fluoro-2–deoxy-D-glucose: validation of method. Ann Neurol 1979;6:371–388. 9. Chugani HT, Phelps ME, Mazziotta JC. Positron emission tomography study of human brain functional development. Ann Neurol 1987;22(4): 487–497. 10. Kinnala A, Suhonen-Polvi H, Aarimaa T, et al. Cerebral metabolic rate for glucose during the first six months of life: an FDG positron emission tomography study. Arch Dis Child (Fetal Neonatal Ed) 1996;74:F153–157. 11. Kinnala A, Nuutila P, Ruotsalainen U, et al. Cerebral metabolic rate for glucose after neonatal hypoglycaemia. Early Human Dev 1997;24:63–72. 12. Suhonen-Polvi H, Ruotsalainen U, Kinnala A, et al. FDG-PET in early infancy: simplified quantification methods to measure cerebral glucose utilization. J Nucl Med 1995;36:1249–1254. 13. O’Tuama LA, Guilarte TR, Douglass KN, et al. Assessment of ll-C-Lmethionine transport into the human brain. J Cereb Blood Flow Metab. 1998;8:341–345. 14. Robinson RO, Ferrie CD, Capra M, Maisey MN. Positron emission tomography and the central nervous system. Arch Dis Child 1999;81(3):263–270. 15. Tokumaru AM, Barkovicha AJ, O’uchia T, Massuo T, Kusano S. The evolution of cerebral blood flow in the developing brain: evaluation with iodine-123 iodoamphetamine SPECT and correlation with MR imaging. AJNR 1999;20(5):845–852. 16. Ogawa A, Sakurai Y, Kayama T, Yoshimoto T. Regional cerebral blood flow with age: changes in rCBF in childhood. Neurol Res 1989;11(3):173–176. 17. Zhang L, Thomas KM, Davidson MC, Casey BJ, Heier LA, Ulug AM. MR quantitation of volume and diffusion changes in the developing brain. AJNR 2005;26(1):45–49. 18. Filippi CG, Lin DD, Tsiouris AJ, et al. Diffusion-tensor MR imaging in children with developmental delay: preliminary findings. Radiology 2003; 229(1):44–50.

L.A. O’Tuama and P.R. Jolles 19. Mukherjee P, Miller JH, Shimony JS, et al. Diffusion-tensor MR imaging of gray and white matter development during normal human brain maturation. AJNR 2002;23(9):1445–1456. 20. Hedlund GL. Neuroradiology of the central nervous system in childhood. Neurol Clin 2002;20(4):965–981. 21. Tanner SF, Cornette L, Ramenghi LA, et al. Cerebral perfusion in infants and neonates: preliminary results obtained using dynamic susceptibility contrast enhanced magnetic resonance imaging. Arch Dis Child (Fetal Neonatal Ed) 2003;88(6):F525–530. 22. Vigneron DB, Barkovich AJ, Noworolski SM, et al. Three-dimensional proton MR spectroscopic imaging of premature and term neonates. AJNR 2001;22(7):1424–1433. 23. Chugani HT. PET scanning Studies of human brain development and plasticity. Dev Neuropsychol 1999;16(3):379–381. 24. Helmstaedter C, Elger CE. Functional plasticity after left anterior temporal lobectomy: reconstitution and compensation of verbal memory functions. Epilepsia 1998;39(4):399–406. 25. Stabin MG, Gelfand MJ. Dosimetry of pediatric nuclear medicine procedures. Q J Nucl Med 1998;42(2):93–112. 26. Santosh P. Neuroimaging in child and adolescent psychiatric disorders. Arch Dis Child 2000;82(5):412–419.

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19 Neurodevelopmental and Neuropsychiatric Disorders Marianne Glanzman and Josephine Elia

Positron emission tomography (PET) and single photon emission computed tomography (SPECT) scans offer great promise in helping to unravel the scientific basis for neurodevelopmental and neuropsychiatric disorders. To date, results have been somewhat limited by the difficulty in obtaining adequate control groups, technical difficulties in studying children, small numbers of subjects, variable analytic methods, and the inability to repeat scans in order to understand the effects of development and intervention due to concerns about exposure to radiopharmaceuticals. Nonetheless, some consistent findings have emerged, and intriguing new results point toward future directions of study.

Attention-Deficit/Hyperactivity Disorder Background Attention-deficit/hyperactivity disorder (ADHD) is one of the most common neurodevelopmental/neuropsychiatric disorders of childhood, with a prevalence of between 5% and 12% in school-aged children, and persistence into adulthood in 50% to 75% of cases (1,2). It is characterized by age-inappropriate difficulty in sustaining mental effort, excessive distractibility, restlessness or overactivity, and impulsivity that is chronic, present across settings, functionally impairing, and not due primarily to another diagnosis such as cognitive or language impairment, autism, mood or anxiety disorders, or medical or other neurologic disorders. Its symptoms have important functional implications for learning, socializing, self-esteem, educational and occupational achievement, driving safety, risk for depression, and the stability of employment and significant relationships. Though “invisible,” it typically has tremendous impact on the lives of the affected individual and family members; thus, improvement in our understanding of its nature and treatment is critical. Neuropsychological testing of individuals who demonstrate the behavioral criteria for ADHD typically reveals evidence of executive 334

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dysfunction. Executive functions are prefrontal cortical functions including sustaining and shifting attention, vigilance, organization, planning, self-monitoring, conception of time, and the ability to inhibit behavior as well as modify it based on past experience and future expectations. Attention-deficit/hyperactivity disorder is highly heritable, and there are probably several genes that confer susceptibility. The most important ones are likely yet to be discovered, though specific alleles at the loci for the dopamine transporter (DAT), dopamine type 4 receptor, and dopamine type 5 receptor appear to be associated (3). Converging evidence from neuropsychological, neurochemical, electrophysiologic, and neuroimaging studies indicate that ADHD is most likely the result of altered dopamine (DA) and norepinephrine neurotransmission in the prefrontal cortex and its targets, particularly the basal ganglia (2,4). Structural imaging studies done for clinical purposes, such as computed axial tomography (CAT) or magnetic resonance imaging (MRI) scans, are not typically revealing in children with ADHD. However, volumetric MRI scans document alterations in the size of various brain regions in subjects compared with controls. Consistent findings include smaller frontal lobes (most notable on the right), globus pallidus, corpus callosum (most often anteriorly), and the posterior inferior cerebellar vermis. The caudate nucleus in subjects with ADHD is also consistently different from that in controls, but the findings between studies are more complex and variable, with some authors reporting a smaller caudate on one side or the other or an absence or reversal of the typical “left greater-than right” asymmetry (5,6). The most recent studies show that, although frontostriatal regions continue to be most markedly implicated, there is a widespread volume loss of approximately 5% to 9% involving both gray and white matter, consistent with involvement of widespread attention and cognitive processing networks (5,7). A developmental study comparing volumetric analysis from children with ADHD and controls across the age span of 5 to 18 indicates that cerebellar, cerebellar vermis, caudate, and gray and white matter from all four cerebral lobes are smaller in subjects from the youngest ages. With correction for total cerebral volume, the cerebellar vermis remained smaller in subjects. The differences remained throughout childhood, with the exception that caudate volumes were similar by 18 due to the lack of the “normal” decline in size in subjects (7). In individual studies, the degree of volume reduction in one or more regions may correlate with specific symptoms or severity, but across studies, findings are somewhat inconsistent (5). This highlights the need for a functional imaging approach. Many functional imaging studies support the role of the prefrontal cortex in working memory, one of the executive functions that is often impaired in individuals with ADHD (4,8). In general, subjects with ADHD are found to activate frontal areas to a lesser degree than controls when performing a memory/attention demanding task, but may activate a wider, more posterior (and behaviorally less effective) set of neural networks to accomplish the task (4,5).

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Three studies using functional MRI (fMRI) in children with ADHD have been reported. These lend support to the role of frontostriatal differences in ADHD, though these studies employed behavioral inhibition rather than working memory tasks during scanning. Rubia et al. (9) studied seven adolescent boys with ADHD and matched controls during two different motor tasks involving pushing a button in response to a target on a screen—one demanding motor inhibition and one stressing motor timing. On the response inhibition task, subjects demonstrated increased right inferior and mid-prefrontal and left caudate activation compared with controls. On the motor timing task, subjects demonstrated decreased right mid-prefrontal activation compared with controls. Vaidya et al. (10) used a “go/no go” task in which subjects responded by pressing a button either to all letters presented on a screen (go task) or all letters except X (no go task). Two different formats were used for the “go” task involving different rates of presentation. This was used as the “control” condition from which to compare activation during the “no go” condition. Different results were obtained with the two different formats, highlighting the importance of slight differences in the behavior portion of the experimental protocol in fMRI results. In the stimulus-controlled, more demanding presentation rate, striatal activation was greater in controls than subjects, and medication typically used to treat ADHD (methylphenidate, MPH) given prior to the task, increased activation in subjects and decreased it in controls. Methylphenidate increased frontal activation in both groups. In the response-controlled, less demanding presentation rate, subjects had more frontal activation than controls and there were no effects of MPH (4). Durston et al. (5) studied the effects of increasing the number of “go” trials that preceded a “no go” trial on the likelihood of making a “no go error” in adults, in typically developing children, and in children with ADHD. In normally developing children, increasing the number of “go” trials before a “no go” trial increased the likelihood of a “no go” error; this effect of interference improved with maturity. In adults, the maintenance of accurate performance with increasing interference resulted in increased activation of the ventral prefrontal cortex, but in children any level of interference results in maximal increases in activation of this area. Seven school-aged, righthanded children with ADHD were compared with matched controls and were found to have similar accuracy and reaction times on the “go” trials. However, though accuracy on the “no go” trials decreased with increasing preceding “go” trials in controls, in subjects even one preceding “go” trial significantly decreased accuracy on a subsequent “no go” trial. When compared with controls, subjects showed less activation in ventral prefrontal cortex, anterior cingulate gyrus, and basal ganglia, and increased activation in posterior parietal and occipital cortices (5). PET/SPECT Imaging in ADHD The first SPECT studies of ADHD were performed in children with ADHD by Lou and colleagues (11) from 1984 to 1990. These studies

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employed xenon-133 (133Xe) inhalation to reflect regional perfusion in children with ADHD; however, these studies were initially criticized because many of the children had coexisting disorders such as language delays. Initial results indicated bilateral central frontal hypoperfusion and occipital hyperperfusion, and MPH treatment was found to increase perfusion in the frontal regions, basal ganglia, and mesencephalon while decreasing it in cortical sensorimotor regions. In later studies, this group employed controls and evaluated subjects with pure ADHD separately from those with language disorders, though the pure ADHD group still may have had more generalized neurologic dysfunction than children typically referred to as having pure ADHD today (12,13). The results were similar with the additional finding in ADHD of decreased perfusion in the striatum (more so on the right). Once again, scans taken after acute MPH treatment tended to show normalization of both under- and overperfusion. In 1990 Zametkin and colleagues (14) undertook a series of PET studies initiated by landmark research often used to the present to prove the biologic basis of ADHD. They used fluorine-18 (18F)-fluoro2-deoxy-D-glucose (18F-FDG) to measure regional cerebral glucose metabolism (rCGM) in 25 adult subjects carefully diagnosed as having persistent ADHD from childhood and 50 matched controls during performance of an auditory continuous performance task that taxed attention, persistence of mental effort, and working memory (though there may have been ceiling effects in terms of its clinical difficulty). Adults with ADHD had an overall 8% decrease in global CGM and 30 of 60 measured regions were lower in subjects, with the largest reductions in the superior prefrontal and premotor cortices. This study was repeated in a smaller number of adolescents, with the expectation that even greater differences from controls would be found in the more clinically symptomatic adolescents, but this was not the case. Left anterior frontal perfusion was found to correlate inversely with symptom severity, however (15). Subsequent studies by this group suggested that females with ADHD might have more pronounced PET findings than males, though findings were not consistent (16–18). During this time frame, other researchers using methods to evaluate regional perfusion or glucose metabolism also found decreased prefrontal cortical perfusion in subjects with ADHD compared with controls (19,20). Sieg et al. (19) also found decreased temporal perfusion using N-isopropyl-123piodoamphetamine (123I-IMP) SPECT in children with normal structural MRIs, some of whom had learning differences. Amen and Carmichael (20) found that subjects actually showed a decrease in prefrontal perfusion (the opposite of what was expected from studies of controls) during an attention-demanding task. More recent studies employing ligands related to general perfusion continue to show decreases in frontal or frontotemporal perfusion in children with ADHD compared with controls, but the laterality of findings differs between studies, perhaps related to differences in learning profiles or coexisting conditions among subject groups (21–24). Even within a study, perfusion abnormalities differ among subjects (21). Decreases in temporal lobe

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perfusion may be related to the presence of coexisting conditions. Lorberboym and colleagues (23) studied young adolescent boys with “pure” ADHD, ADHD plus oppositional, conduct, learning, or mood disorders, and controls during a computerized continuous performance task using technetium-99m ethylcysteinate dimer (99mTc-ECD) SPECT. Although there were differences among subjects, all subjects with an additional diagnosis had decreased perfusion in one or both temporal lobes. Several studies have also been done using ligands related to specific neurotransmitters rather than glucose utilization or perfusion. Ernst and colleagues (25,26) used 18F-fluorodopa (18F-FD) to assess the integrity of DA uptake processes in the midbrain, striatum, and prefrontal cortex of adults and children with ADHD compared with controls. Adults showed more than a 50% decrease in uptake in medial and lateral prefrontal cortex (25), whereas children showed an almost 50% increase in the right midbrain (26). The most common neurotransmitter component studied in ADHD is DAT. Methylphenidate, the most commonly prescribed medication for treating ADHD, blocks dopamine reuptake at the transporter (27). Many types of studies implicate the DA system in ADHD symptoms (28,29), and genetic studies implicate DAT polymorphisms in ADHD (30). Several studies (31–33), though not all (34), have found elevated levels of DAT binding in adults with ADHD; one study in children (35) showed that medication-naive children with ADHD have 14% to 70% increases in DAT binding in the striatum compared with controls. In summary, decreased perfusion in the frontal lobes and basal ganglia are typically found in subjects with ADHD compared with controls. Subjects tend to activate more widespread neural networks in response to attention-demanding tasks. Findings between studies differ with respect to laterality (5,21–24). Findings in children and adults show both similarities and differences, but developmental changes over the course of childhood have not been well studied. Gender differences are likely to be important but require further study. Finally, the small numbers of subjects has limited the ability of researchers to separate the findings specifically related to ADHD from those related to commonly coexisting conditions, but work is beginning in this direction. PET/SPECT Imaging and Medications for ADHD Stimulants have been used for decades and are the treatment of choice for ADHD. There are two categories of stimulants, MPH and amphetamine (AMPH), with a variety of products available in each category with different durations of action and release properties. Functional imaging studies investigating medication effects have typically been performed with short-acting (3 to 4 hours) MPH or dextroamphetamine (d-AMPH) even though most children actually take longer-acting formulations. Strattera, a selective norepinephrine reuptake inhibitor, was recently approved for the treatment of ADHD (36). To date, there are no functional imaging studies of its effects in children with ADHD.

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Approximately 30% of students with ADHD do not respond to or do not tolerate stimulants due to side effects (27). The presence of comorbidities related to mood and anxiety, and repetitive behaviors such as tics or compulsions may increase the risk for medication side effects or limit stimulant effectiveness (37). Alternative medications, including antidepressants, antihypertensives, atypical antipsychotics, and modafinil (a medication approved for narcolepsy) are sometimes used in these children but have not been studied with functional imaging in children with ADHD. Matochik et al. (38,39) evaluated the effects of acute and subchronic (6 week) MPH and d-AMPH on rCGM in adults with ADHD using 18FFDG. There was no change in global metabolism in any condition, and very few changes at all were noted with subchronic administration. With acute administration, some regions increased and others decreased, not necessarily in the pattern that would have been expected based on previous studies reported herein. The findings with MPH and d-AMPH differed, even though behavioral improvements were similar. Schweitzer et al. (40) compared rCBF using oxygen-15 (15O)-H2O in adults with ADHD before and after 3 weeks of optimally dosed MPH. In conjunction with improved behavioral measures, posttreatment scans showed higher rCBF in the posterior cerebellum and decreased rCBF in the bilateral precentral gyrus, left caudate, and right claustrum. Volkow et al. (41) also noted differences between acute and chronic administration. They also showed that, in healthy adults, the regions activated by MPH administration, as demonstrated by 18F-FDG uptake, differed between subjects with high and low DA type 2 (D2) receptor binding assessed concomitantly with 11C-raclopride (42). Mattay et al. (43) administered d-AMPH during neuropsychological tasks that taxed different brain regions and measured rCBF with 15 O-H2O. d-AMPH was found to increase rCBF in a task-dependent manner. Thus, characteristics of the subjects or the brain activity during scanning may influence results. Two studies have investigated the effects of MPH in children and adolescents with ADHD using PET/SPECT scanning. Szobot et al. (44) measured blood flow with 99mTc-ECD before and after 4 days of MPH or placebo treatment in 36 boys with ADHD without severe comorbidities (but boys with oppositional defiant disorder and learning disorders were not excluded). Statistical parametric mapping showed a decrease in the left parietal region in the treated group compared with the placebo group, suggesting that the posterior attentional system may also be involved in the behavioral effects of MPH. Langleben et al. (45) studied the effects on rCBF of discontinuing MPH in boys with ADHD and controls with 99mTc-ECD SPECT and found increased rCBF in the motor, premotor, and anterior cingulated cortices, but this study was not designed in such a way as to determine whether ADHD treatment lowers rCBF in these areas, or whether the increase was a specific response to withdrawal of subchronic treatment. Several researchers have evaluated the effects of MPH on the DAT and other specific measures of DA function using PET/SPECT scans.

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Volkow and colleagues (46) have shown that (1) oral MPH reaches peak concentrations in the brain at 60 to 90 minutes, (2) therapeutic doses block about 50% of striatal DATs, (3) MPH’s relatively slow uptake and egress from the brain is most likely responsible for its lack of euphorogenic properties in contrast to cocaine, and (4) it is the d-isomer of MPH that effectively blocks the DAT. Furthermore, they have shown that DAT blockade leads to increased extracellular DA in the striatum and that variability in response to MPH is more likely due to variability between individuals in their dopaminergic neuronal activity, which modulates the degree of extracellular DA increase in response to DAT blockade rather than differences in the degree of MPH-induced DAT blockade itself (46). Researchers have also begun to think about how to use PET/SPECT to assess the long-term effects of medication on the dopamine system. Vles et al. (47) studied six, non-comorbid, medication-naive boys with ADHD at baseline and after 3 to 4 months of clinically optimized MPH treatment. Behavior and neuropsychological test performance improved. They used 123I-loflupane (FP-CIT) to label DAT and 123Ibenzamide (IBZM) to label postsynaptic D2 receptors in the caudate and putamen. Due to the small number of subjects, only descriptive statistics are used. At baseline, D2 receptor binding was similar in the left and right caudate and putamen. After 3 months of treatment, five of the six subjects showed a decrease (average of 14%) in D2 receptor binding in the striatum. One subject was re-scanned after 1 month off medication, and his D2 receptor binding returned to pretreatment levels. Baseline DAT binding was less in the left compared to right caudate in all six subjects. Whether this reflects normal development or is characteristic of ADHD is still unclear. Binding differences in the left and right putamen varied among subjects. After treatment, binding decreased in both the caudate and putamen by an average of 58% and the left < right asymmetry disappeared. In the subject who was scanned after a month off medication, binding in the right caudate and putamen returned to pretreatment levels, but binding in the left caudate and putamen was increased by 30% and 50%, respectively. This study suggests that further study is warranted regarding the possibility of long-term alterations in DAT function as a result of MPH treatment. Ilgin et al. (48) evaluated D2 receptor availability in the caudate and putamen of medication-naive children with ADHD before and after 3 months of MPH treatment. At baseline, subjects demonstrated normal to increased D2 receptor binding compared to published values for healthy young adults. It is known that D2 receptor binding decreases with age, but even taking this into account, these values were higher than anticipated. However, the lack of age-matched controls in the same study makes any conclusions about higher D2 receptor binding in children with ADHD preliminary. No right/left asymmetry in binding was detected in either region. Chronic medication effect studies are critical but are complicated by the need for controls for normal developmental changes and potential differences in effects of long- and short-acting medications.

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Tourette Syndrome Background Tourette syndrome (TS) is the most complex form of tic disorder and occurs in approximately 0.1% to 1% of children. Tics are brief, repetitive, staccato, involuntary movements or vocalizations that tend to occur in clusters, and typically fluctuate in type, frequency, and severity over time. It is diagnosed when an individual displays multiple motor tics and at least one vocal tic that fluctuate in character and severity over time, have persisted for more than a year, and have not occurred solely during the course of treatment with a medication that is known to induce or exacerbate tics (e.g., stimulants for ADHD). Other tic disorders, which occur more commonly than full TS, include chronic single tic disorder (1% to 2% of children) and transient tic disorder (approximately 5% of children) (49,50). Chronic tic disorders of any variety, however, appear to be genetically related (51,52). Although most cases of TS are mild in terms of tic severity and tic-related functional impairment, it is common for individuals with TS to have comorbidities that are far more functionally impairing including ADHD, obsessive-compulsive disorder (OCD), other forms of anxiety, aggression, and learning disabilities (LDs) (49). Not only do tic disorders of varying severity probably have a common genetic etiology, but there appear to be genetic relationships among tics, ADHD, and OCD as well (53). The search for the genetic etiology of TS has been ongoing for over 20 years, and, as with the genetics of other complex behavioral disorders, progress has been slow. Recently, linkages have been identified on chromosomes 2, 4, 5, 8, 11, and 19, but specific genes in these areas remain to be identified (51). Immune reactions to streptococcal bacteria and other agents that produce antibodies that cross-react with basal ganglia neurons may be etiologic in some cases, and this phenomenon may have genetic underpinnings. Nongenetic factors including uterine and hormonal milieu, and maternal stress during pregnancy may also play a role (49,54). Multiple lines of evidence, including various neuroimaging modalities, support the involvement of the basal ganglia in movement disorders, including TS. However, dyscontrol of movement can occur at any level in cortical–basal ganglia–thalamocortical circuitry. Multiple lines of evidence also indicate a role for the dopamine system in TS, including the effects of medications (dopaminergic medications can exacerbate tics, whereas dopamine-blocking agents are used to treat tics), studies of dopamine metabolites, and functional imaging studies involving dopamine-related ligands. PET/SPECT Imaging in TS Imaging studies of tic disorders have focused on TS; however, the high rate of multiple comorbid conditions in individuals with TS has complicated the interpretation of results. Volumetric MRI studies in adults with TS show decreased size of the prefrontal cortex and left caudate and putamen, whereas children with TS show larger prefrontal

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volumes and left caudate reductions (55). A recent study that used parcellation into more specific subregions of the frontal lobes and distinguished white and gray matter found that boys with TS had decreased volume of the left deep white matter, suggesting abnormalities of association and projection bundles, in contrast to boys with ADHD who were found to have reduced volumes of gray and white matter within the prefrontal cortex (56). Positron emission tomography/SPECT studies assessing regional metabolism or blood flow in TS have been performed in adults, primarily, and have confirmed decreased activity in the striatum in comparison with controls, though specific locations have differed between studies and have included ventral striatum, ventral globus pallidus, and basal ganglia in general. Some, but not all, studies suggest a greater decrease in left-sided structures (55). Other researchers have also found decreases in the midbrain (57), thalamus (58), cingulate, and prefrontal cortex (59) and one group found an increase in frontal CBF (60). Limitations in anatomic resolution may contribute to discrepancies in these studies. In addition, the role of tics themselves and tic suppression during scanning may complicate findings. A study of blood flow in conjunction with tic frequency during scanning indicates that multiple brain areas associated with motor activity as well as several not generally associated with motor activity show increased flow in association with tics (61). Studies under the identical conditions assessing similar voluntary motor behaviors would need to be done to identify the regions associated specifically with tic generation as opposed to the motor activity itself. Finally, areas activated or deactivated by the acute or chronic process of suppressing tics are largely unknown and may be relevant to studies of both etiology and changes in findings over the life span. An fMRI study of tic suppression showed that it was associated with increases and decreases in signal in a variety of regions, some unilateral and some bilateral. In particular, prefrontal and right caudate showed increased signal, associated with decreased signal in the rest of the basal ganglia (62). Positron emission tomography/SPECT studies assessing striatal dopaminergic innervation using 18F-FD, 123I-2b-carbomethoxy-3b-(4iodophenyl)tropane (b-CIT), and IBZM have been done primarily in adults and have shown conflicting results, initially thought to be due to potential effects of prior or current medication exposure (55). Initial studies showed increased binding to DAT sites in adults with TS compared with controls (63–65), and a study in children without current medication showed increased 18F-FD activity in the left caudate and right midbrain (66). Later studies controlled for this variable but still showed conflicting results. For example, a study by Stamenkovic et al. (67) evaluated medication-naive and actively medicated subjects (adolescents and primarily young adults) separately and found no increase in DAT binding in either group but more variability among the medicated group. Serra-Mestres et al. (68) found higher 2b-carbomethoxy-3b-(4iodophenyl)-N-(3-fluoropropyl)nortropane (123I-FP-CIT) binding in both caudate and putamen in 10 neuroleptic naive/free adults com-

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pared with controls, but the binding did not correlate with any of the measured indices of TS severity. Other important variables may include past history of medication use and coexisting disorders. In a study that looked more specifically at different anatomic regions within the striatum, Albin et al. (69) studied 19 adults with TS and various medication histories and comorbidities with 11C-dihydrotetrabenazene (11C-DTBZ), a ligand for the type 2 vesicular monoamine transporter. They found no difference compared with controls in the dorsal striatum but an increase in binding in the right ventral striatum. Finally, Cheon et al. (35) studied nine drug-naive children aged 6 to 12 with TS (excluding those with comorbid OCD, ADHD, anxiety, and depression) and matched controls with 123I-N-(3-iodoproprn-2-yl)-2b-carbomethoxy-3b(4-clorophenyl)tropane (123I-IPT) SPECT and found subjects to have an increase in specific to nonspecific (measured in cerebellum) binding in the basal ganglia, though this did not correlate with tic severity. D2 receptor density has been studied with PET/SPECT in adult subjects with TS and generally found not to differ from controls (55), though one study suggests that a subgroup of adults with TS may have an increased binding capacity (70). One study comparing five sets of adult monozygotic twins found a 17% increase in D2 binding capacity in the more severely affected twin (71), and one study found a decrease in D2 binding capacity in subjects affected for more than 15 years and in subjects on neuroleptic medication. Because both of these conditions are associated with a lessening of tic severity, it may be hypothesized that a decline in D2 binding may be associated with symptom improvement (64).

Dyslexia Background Learning disability can be described (as proposed by the National Joint Committee on Learning Disabilities) as a generic term that refers to a heterogeneous group of disorders manifested by significant difficulties in the acquisition and use of listening, speaking, reading, writing, spelling, reasoning, or mathematical abilities. It is intrinsic to the individual and presumed due to dysfunction of the central nervous system and not due to cognitive impairment, sensory dysfunction, inadequate educational exposure, social/emotional disturbance, or environmental disadvantage (72). A learning disability in reading, or dyslexia, is the most common form of learning disability, affecting approximately 10% of children. Many children with dyslexia have associated language, spelling, writing, attention, and fine motor deficits (73). Multiple lines of evidence indicate that three types of underlying processing deficits occur in dyslexia: phonologic, visual, and temporal. The best studied, and most central, is phonologic; children with dyslexia are impaired in their ability to segment words verbally as well as graphically into their component phonemes (sound segments), and, in the reverse, to combine phonemes accurately into words. Visual processing deficits are inferred from the types of reading errors children

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make (substitutions of visually similar letters, words, etc.) as well as studies that show slower visual processing. Temporal processing deficits were identified most recently. Alterations have been found in the magnocellular component of the auditory and visual pathway, known to be relevant for the rapid detection of changes in and sequences of stimuli, and it has been hypothesized that the left hemisphere in particular is involved in the processing of transient sensory events. Studies of event-related potentials suggest that dyslexics are impaired in the distinction between speech sounds in the preattentive phase, as measured by mismatch negativity, and have lower or later P300 waves reflecting inefficient processing of target stimuli (73). Classic studies of language-impaired and dyslexic children by Tallal et al. (74) indicate that they are impaired in distinguishing phonemes that differ by rapid or subtle frequency differences but not those that differ by slower or more prolonged frequency characteristics. This may be true for other sensory modalities as well. Electrophysiologic evidence supports both slower auditory and visual processing in dyslexics (75). It is likely that children with dyslexia differ from each other with respect to the degree of each different type of impairment they manifest. Some may be more phonologically dyslexic, whereas others are more visually dyslexic, though the ultimate clinical impairment is the same. Dyslexia is commonly genetic, but the specific inheritance pattern is unknown. It appears that genes on a variety of different chromosomes may be related to different neuropsychological processes that are weak in dyslexics. For example, a gene on chromosome 15 appears related to rapid single word reading, whereas one on chromosome 6 appears related to a phonologic awareness task (73). A twin study indicates that the phonologic component of dyslexia is more strongly heritable than the visual component (76), supporting a role for the prenatal environment in the latter as has previously been proposed (77,78). Anatomic studies of the brains of dyslexic individuals show two types of consistent abnormalities: ectopias in the bilateral frontal and left temporal and parietal cortices with associated adjacent dysplasia, and loss of the normal left > right size of the planum temporale. These findings indicate that dyslexia is associated with altered mid-gestation brain development. Less frequent findings include vascular micromalformations and microgyria (73). Functional MRI studies of the brain during reading by Shaywitz (79) and others showed that women activate both the left and right inferior frontal gyrus (Broca’s area) while reading, whereas men activate only the left. This part of the brain appears to be specifically involved in sounding out words, as it is activated by the reading of nonsense words. An occipitotemporal region is important in storing information about word form, which allows automatic recognition of words previously accurately analyzed, and a parietotemporal area is important in slowly analyzing words. As readers become more skilled, they activate the occipitotemporal area (automatic word recognition) more and the parietotemporal and frontal areas (word analysis) less. Dyslexic readers have less posterior activation but also show a change in activation

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pattern over the course of development, unlike skilled readers who show more posterior than anterior activation at all ages. Dyslexics increasingly activate the front of the brain as well as right-sided auxiliary pathways as they become adolescents, suggesting that they increasingly compensate for poor word recognition by the slower process of word analysis. These findings are present in dyslexics in all languages and at all ages (79,80). Functional MRI has been used to demonstrate that dyslexics do not activate motion-sensitive regions of the magnocellular system located in the posterior part of the inferior temporal sulcus, which supports the temporal processing theory of dyslexia (81). Functional MRI has also been used to show that effective reading intervention leads to “brain repair” in that in response to the specific type of instruction known to improve reading in dyslexics, and with confirmation of improved skills, dyslexic children show increased activation of the left posterior region similar to that of controls (82,83). PET/SPECT Imaging in Dyslexia Oxygen-15 (15O)-H2O, 18F-FDG, and 133Xe inhalation have been used to study reading and its subprocesses in dyslexics and controls. To date, there have been no studies in children. The vast majority of studies find differences between dyslexics and controls in one or more regions of the brain known to be involved in language or reading, but specific findings cannot be compared across studies because different tasks are used and the coexistence of ADHD has not typically been considered. Different patterns of abnormal left hemisphere blood flow have been found in several studies (84). For example, Flowers et al. (85) found that although language tasks activated the expected supratemporal area (Wernicke’s area) in controls, it activated a slightly posterior temporoparietal area in adults who were poor readers in childhood, perhaps related to additional effort required. In a series of studies by Rumsey and colleagues (86), different types of reading tasks were performed by controls and adult dyslexics. Dyslexics showed reduced activation of the left parietal region at rest, and bilateral reduced activation of the mid-to-posterior temporal cortices and left inferior parietal cortex during phonologic processing tasks. During tasks requiring syntactical (word meaning) processing, dyslexics showed similar activation to controls in the left mid-toanterior temporal lobe and inferior frontal cortex. Gross-Glenn et al. (87) showed symmetry rather than the asymmetry seen in controls in metabolic activity in the prefrontal cortex and lingual area of the occipital lobes during oral reading in adult dyslexic men. Hagman et al. (88) found higher metabolic rates in the medial temporal cortices bilaterally in adults who had been diagnosed with dyslexia in childhood compared with controls during a task taxing attention and speech discrimination. This study and others reviewed by Frank and Pavlakis (84) and McCandiss and Noble (83) suggest that dyslexia may be related to a disconnection between anterior and posterior language areas. In general, adults with dyslexia show underactivation of left

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temporoparietal language processing areas, and in some cases, more symmetry of activation and increased anterior activation. A similar constellation of findings was shown in two proton MRI studies in children with dyslexia. Both showed differences from controls, but one showed a decreased ratio of choline to N-acetylaspartate in the left temporoparietal region (89), whereas the other showed a larger anterior number of voxels with elevated lactate during phonologic tasks (90), again suggesting increased compensatory anterior activity. In addition to differences in age and task requirements, future studies should take into account the remediation history, current types and severity of reading difficulty, and related conditions, especially ADHD and language impairment.

Autism Background Autism, a developmental disorder first described by Kanner in 1943, is characterized by impairment in social reciprocity, language impairment, restricted interests, and repetitive behaviors (91–93). The etiology remain unknown; however, there is some support for genetic, environmental, neurologic, and immunologic factors in its development (93–96). Autistic features can also present in some neurologic disorders such as tuberous sclerosis, neurofibromatosis, fragile X, Rett syndrome, and phenylketonuria (97). Mental retardation co-occurs in 70% of cases and seizures in 33% (97). Epidemiologic studies are suggesting an increase in prevalence of 1 in 250 to 500 children, which is thought to be due to improved and expanded diagnostic criteria (98,99). Abnormalities in cerebral cortex (100), cerebral asymmetry (101), ventricles (97,102,103) and cerebellum (104–107) have been reported in computed tomography (CT) and MRI scans. Clinical manifestations usually emerge between ages 2 and 4 and may reflect abnormal brain development (108). As reviewed by Courchesne et al. (108,109), accelerated head circumference from birth to age 2 in autistic children may reflect rapid brain overgrowth. Brain volumes in autistic children ages 2 to 3, measured by MRI, show an enlargement in the frontal, parietal white matter volumes, and frontal and temporal gray matter. This is in contrast to the cerebellar hypoplasia (primarily posterior vermis) noted in autistic children and adolescents. Between ages 5 and 12, brain volumes in autistic children compare to those of normal children, suggesting an abnormally decelerated growth pattern. PET/SPECT Imaging in Autism A review by Boddaert and Zilbovicius (110) of PET/SPECT studies conducted at rest in autistic subjects show mixed results including increased global metabolism (111–113), bitemporal hypoperfusion (114,115) and temporofrontal hypoperfusion (116,117), whereas others found no localized abnormalities (118–120). Autistic children were the

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focus of several of these studies (112,114,116,119,120) with one including autistic subjects with seizures (116). Zilbovicius et al. (121) conducted the first longitudinal study, measuring rCBF twice during development (age 2 to 4 and then at ages 6 to 7) in the same group of five autistic children matched to five nonautistic children with normal development. Frontal hypoperfusion was found in the autistic group at ages 3 to 4 that normalized by the time these children reached 6 to 7 years of age. Functional brain imaging has also been conducted during various tasks aimed at elucidating cortical activation patterns involved in language, cognitive, and emotional functions. A well-controlled PET study using 15O-H2O found differences in thalamic blood flow and the dentate-thalamocortical pathway in four autistic men compared with five healthy controls performing an expressive language task (122). Another study in seven autistic patients and seven sex- and agematched controls evaluated with both PET and MRI while performing a serial verbal learning task, showed decreased glucose metabolism in the right anterior cingulate cortex (specifically in Brodmann’s area 24’, which is thought to be involved in executive functions and information processing) (123,124). These investigators increased their study sample to 10 individuals with autism and seven individuals with Asperger’s syndrome—an autistic spectrum disorder in which there is normal language development but abnormalities in pragmatic language, impairment in nonverbal communication and social interaction, and restricted interests or activities. Patients were compared to 15 men and two women controls, using 18F-FDG uptake, and smaller volumes for right anterior cingulate gyrus were identified. The authors divided the anterior cingulate gyrus into three segments (Brodmann’s areas 25, 24, and 24’), and Brodmann’s area 24’ was found to be significantly smaller in patients with autism. No volume differences were noted for the left anterior and posterior cingulate gyri. No significant differences were found in glucose metabolic rate of the amygdala or hippocampus. Significantly lower glucose metabolism was found in both the anterior and posterior cingulate gyri in the autistic group. Patients with Asperger’s syndrome had bilateral glucose hypometabolism in the anterior cingulate cortex compared to controls, whereas the autistic patients differed only in the right anterior cingulate gyrus. Within the autistic and Asperger groups, hypometabolism was found in the right posterior cingulate gyrus in autistic patients, whereas hypometabolism was bilateral in Asperger patients (125). Garreau et al. (126) performed the first activated SPECT study in autistic children and found activation in the right posterior associative cortex in contrast to the control group in which left-sided activation was seen. Studies of auditory cortical processing using 15O-H2O PET in five autistic adults and eight controls at rest and while listening to speech-like sounds found bilateral activation of the superior temporal gyrus in both groups. However, in the autistic group there was significantly greater activation in the right middle frontal gyrus and less activation in the left temporal area, suggesting a dysfunction of temporal

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regions specializing in perception and integration of complex sounds (127). The same investigators (Zilbovicius et al.), using the same PET technique, reported essentially similar results in a group of 11 autistic children. They found that although significant activation of the auditory cortex in the bilateral superior temporal gyrus (Brodmann’s area 22) occurred in both groups while subjects were listening to speech-like stimuli, control children activated the superior temporal cortex bilaterally with left-biased asymmetry. This left dominance, not observed in the autistic groups, suggests abnormal auditory cortical processing (128). In another PET study of 33 autistic children compared to 10 nonautistic children with idiopathic mental retardation, the same group of investigators found significant hypoperfusion of both temporal lobes (114). Using SPECT, Ohnishi et al. (115) reported hypoperfusion bilaterally in the superior temporal gyrus and in the left frontal region in 23 autistic children compared with 26 control children. Muller et al. (129) scanned five autistic individuals and five normal controls, using 15O-H2O at rest, while the subjects were listening to tones and listening, repeating, and generating sentences. The autistic group had reversed hemispheric dominance during verbal auditory stimulation, a trend toward reduced activation of auditory cortex during acoustic stimulation, and reduced cerebellar activation during nonverbal auditory perception. A reanalysis of these studies focusing on brain regions identified in previous studies [left thalamus, dorsolateral prefrontal cortex, dentate nucleus (130)] showed reduced activation in the right dentate nucleus and left frontal area 46 during a verbal auditory and expressive language task that increased during motor speech (122). Patterns of brain activity measured in normal volunteers while reading stories involving complex mental states, nonmental stories, and unconnected sentences showed the left medial prefrontal cortex (on the border between Brodmann areas 8 and 9) as the brain area specifically associated with “mentalizing” story comprehension (131). Autistic individuals may do well on cognitive tasks but lack the ability to attribute mental states to themselves or others (explain and predict the behavior of others in terms of their beliefs or desires) (132). Five adult men with Asperger’s syndrome and normal volunteers were scanned using a CTI model 953B PET scanner (CTI, Knoxville, USA) after receiving a bolus of 15O-H2O. Results showed that individuals with Asperger’s syndrome performed as well as controls with unlinked sentences but performed worse on the story conditions. The PET scans showed activation in most of the same brain areas [temporal pole (left), temporal pole (right) and angular gyrus (left)] with one exception—the medial frontal cortex (133). Serotonin abnormalities reported in autism include increased blood serotonin (134), symptom exacerbation with tryptophan depletion (135), and improvement with serotonin reuptake inhibitors (136– 138). Positron emission tomography studies using a-11C-methyl-Ltryptophan that allows direct in vivo measurement of serotonin

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synthesis in humans have shown an asymmetry of serotonin synthesis in the frontal cortex, thalamus, and cerebellum in autistic boys compared with normal controls (130). Using the same method, these investigators measured serotonin synthesis capacity in 24 boys and six girls with autism and eight of their siblings as well as 16 children with epilepsy. In the nonautistic children, serotonin synthesis capacity was more than 200% of adult values until age 5 and then declined toward adult levels, with the decline occurring earlier in girls than in boys. In autistic children, serotonin synthesis capacity increased gradually between the ages of 2 and 15 to values one and a half times adult values; no gender differences were noted (139). Using a cluster analysis of autism subscales, significant differences in a-11C-methyl-Ltryptophan uptake was noted between the two clusters (stereotyped behavior and social isolation subscales) in the right cerebellar cortex, cerebellar vermis, dentate nucleus, and pineal gland (140). This may be of significance given that areas of the dentate-thalamocortical pathway in the dorsolateral prefrontal lobe are thought to be involved in language processing (141). In summary, findings from earlier functional brain imaging studies in autism did not detect consistent abnormalities, but none had used both PET and MRI to localize precise anatomic differences in metabolic activity patterns that distinguished autistics from controls. More recent, well-controlled studies have shown bilateral hypoperfusion of the temporal lobes and abnormal patterns of thalamocortical activation. These brain areas, thought to be involved in language and emotional function, may be sites of pathologic processes in autism. The lack of age normative data and the frequent occurrence of other conditions also affecting brain function (different levels of mental retardation, seizures) have also impeded interpretation of PET data.

Anxiety and Mood Disorders Anxiety disorders occur in 5% to 15% of children and can be classified as one or more of several types including separation anxiety, overanxious disorder, panic disorder, specific phobias, and OCD (142). There are no PET studies in children with anxiety disorders. In adult studies, anxiety symptoms provoked in healthy controls result in increased regional cerebral metabolic rate (rCMR) (measured as glucose uptake) in the orbitofrontal, temporal, and cuneus gyri, left anterior cingulate and inferior frontal gyri, and left insula. Also the rCMR for glucose (rCMRGlu) is decreased in the right posterior temporoparietal, superior frontal, and medial frontal cortices (143,144). A review by Osuch et al. (145) of functional brain imaging in adults with anxiety disorders indicates involvement of several brain areas including increased cerebral blood flow and metabolism in the right compared to the left parahippocampal gyrus (146–148). A comparison of patients with anxiety disorders and healthy volunteers found flumazenil volume distribution lower in anxiety patients

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in all areas sampled (149). A 20% decrease in benzodiazepine binding was reported in patients with panic disorder using 11C-flumazenil localized primarily to the orbitofrontal, anterior insula, and anterior temporal cortices, brain areas thought to play role in anxiety (150). A PET study investigating serotonin type 1A receptor [5-hydroxytryptamine type 1A receptor (5HT1AR)] binding in patients with panic disorder shows marked reduction in the anterior and posterior cingulate cortices (151). Symptom provocation studies in OCD, simple phobia, and posttraumatic stress disorder (PTSD) showed increased cerebral metabolism in the insular cortex, right frontal and posterior medial orbitofrontal cortices, and lenticular nucleus (152). Decreased cerebral blood flow was reported in superior frontal cortices and right caudate in OCD and PTSD (153). Studies with medications and behavioral therapy used to treat some of the anxiety disorders also give us some insight. In patients with OCD, chronic administration of fluoxetine or clomipramine improved OCD symptoms and normalized abnormally elevated rCMRGlu in the right head of the caudate and orbitofrontal regions (areas thought to be involved in OCD symptomatology). Behavioral therapy produced similar results as medications (154–156). Eighteen adults with childhood-onset OCD were studied using 18F-FDG. Increased glucose metabolism was found in the OCD group in left orbital frontal, right sensorimotor, and bilateral prefrontal and anterior cingulate cortices compared to controls. There was a significant relationship between metabolic activity, state and trait measurements of OCD and anxiety, and response to clomipramine (157). There are no PET studies of children with mood disorders; however, in studies of adults PET scans are proving to be useful in exploring these conditions. As reviewed by Videbech (158), although PET studies in adult patients with major depression have many limitations, some consistent results include reduced blood flow and glucose metabolism in the prefrontal cortex (159–162), anterior cingulate cortex (163), and caudate nucleus (159,164) during rest as well as during cognitive tasks. Increased blood flow and metabolism was reported in the amygdalae of depressed patients (164–166). Recovery has been associated with normalization of reduced glucose metabolism of the prefrontal cortex (160,161,167), cingulated cortex (168), and caudate nucleus (159). Increased blood flow in the amygdala may be a trait marker because it persists after recovery (164). Decreased blood flow and metabolic rate has been reported in depressed patients with bipolar disorder (159,161) and not in unipolar depression (169,170). A PET study of patients with depression and anxiety showed that comorbid anxiety was associated with specific metabolic findings that differ from those found in patients with depression alone (145). Successful psychotherapy has also been shown to result in adaptive regional brain metabolic changes (171,172). Because depression commonly develops in adolescents and young adults, it would be useful to use PET technology to identify trait or predictive findings in those at risk, as well as those that signal active depression, treatment response, and recovery.

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M. Glanzman and J. Elia 118. Herold S, Frackowiak RS, Le Couteur A, Rutter M, Howlin P. Cerebral blood flow and metabolism of oxygen and glucose in young autistic adults. Psychol Med 1988;18(4):823–831. 119. Zilbovicius M, Garreau B, Tzourio N, et al. Regional cerebral blood flow in childhood autism: a SPECT study. Am J Psychiatry 1992;149(7): 924–930. 120. Chiron C, Leboyer M, Leon F, Jambaque I, Nuttin C, Syrota A. SPECT of the brain in childhood autism: evidence for a lack of normal hemispheric asymmetry. Dev Med Child Neurol 1995;37(10):849–860. 121. Zilbovicius M, Garreau B, Samson Y, et al. Delayed maturation of the frontal cortex in childhood autism. Am J Psychiatry 1995;152(2):248–252. 122. Muller RA, Chugani DC, Behen ME, et al. Impairment of dentatothalamo-cortical pathway in autistic men: language activation data from positron emission tomography. Neurosci Lett 1998;245(1):1–4. 123. Devinsky O, Morrell MJ, Vogt BA. Contributions of anterior cingulate cortex to behaviour. Brain 1995;118(pt 1):279–306. 124. Haznedar MM, Buchsbaum MS, Metzger M, Solimando A, Spiegel-Cohen J, Hollander E. Anterior cingulate gyrus volume and glucose metabolism in autistic disorder. Am J Psychiatry 1997;154(8):1047–1050. 125. Haznedar MM, Buchsbaum MS, Wei TC, et al. Limbic circuitry in patients with autism spectrum disorders studied with positron emission tomography and magnetic resonance imaging. Am J Psychiatry 2000;157(12): 1994–2001. 126. Garreau B, Zilbovicius M, Guerin P. Effects of auditory stimulation on regional cerebral blood flow in autistic children. Dev Brain Dysfunction 1994;7:119–128. 127. Boddaert N, Belin P, Chabane N, et al. Perception of complex sounds: abnormal pattern of cortical activation in autism. Am J Psychiatry 2003;160(11):2057–2060. 128. Boddaert N, Chabane N, Belin P, et al. Perception of complex sounds in autism: abnormal auditory cortical processing in children. Am J Psychiatry 2004;161(11):2117–2120. 129. Muller RA, Behen ME, Rothermel RD, et al. Brain mapping of language and auditory perception in high-functioning autistic adults: a PET study. J Autism Dev Disord 1999;29(1):19–31. 130. Chugani DC, Muzik O, Rothermel R, et al. Altered serotonin synthesis in the dentatothalamocortical pathway in autistic boys. Ann Neurol 1997; 42(4):666–669. 131. Fletcher PC, Happe F, Frith U, et al. Other minds in the brain: a functional imaging study of “theory of mind” in story comprehension. Cognition 1995;57(2):109–128. 132. Baron-Cohen S, Leslie AM, Frith U. Does the autistic child have a “theory of mind”? Cognition 1985;21(1):37–46. 133. Happe F, Ehlers S, Fletcher P, et al. “Theory of mind” in the brain. Evidence from a PET scan study of Asperger syndrome. Neuroreport 1996;8(1):197–201. 134. Schain RJ, Freedman DX. Studies on 5–hydroxyindole metabolism in autistic and other mentally retarded children. J Pediatr 1961;58:315–320. 135. McDougle CJ, Naylor ST, Cohen DJ, Aghajanian GK, Heninger GR, Price LH. Effects of tryptophan depletion in drug-free adults with autistic disorder. Arch Gen Psychiatry 1996;53(11):993–1000. 136. Gordon CT, State RC, Nelson JE, Hamburger SD, Rapoport JL. A doubleblind comparison of clomipramine, desipramine, and placebo in the treatment of autistic disorder. Arch Gen Psychiatry 1993;50(6):441–447.

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M. Glanzman and J. Elia 155. Schwartz JM, Stoessel PW, Baxter LR Jr, Martin KM, Phelps ME. Systematic changes in cerebral glucose metabolic rate after successful behavior modification treatment of obsessive-compulsive disorder. Arch Gen Psychiatry 1996;53(2):109–113. 156. Swedo SE, Pietrini P, Leonard HL, et al. Cerebral glucose metabolism in childhood-onset obsessive-compulsive disorder. Revisualization during pharmacotherapy. Arch Gen Psychiatry 1992;49(9):690–694. 157. Swedo SE, Schapiro MB, Grady CL, et al. Cerebral glucose metabolism in childhood-onset obsessive-compulsive disorder. Arch Gen Psychiatry 1989;46(6):518–523. 158. Videbech P. PET measurements of brain glucose metabolism and blood flow in major depressive disorder: a critical review. Acta Psychiatr Scand 2000;101(1):11–20. 159. Baxter LR Jr, Phelps ME, Mazziotta JC, et al. Cerebral metabolic rates for glucose in mood disorders. Studies with positron emission tomography and fluorodeoxyglucose F 18. Arch Gen Psychiatry 1985;42(5): 441–447. 160. Baxter LR Jr, Schwartz JM, Phelps ME, et al. Reduction of prefrontal cortex glucose metabolism common to three types of depression. Arch Gen Psychiatry 1989;46(3):243–250. 161. Martinot JL, Hardy P, Feline A, et al. Left prefrontal glucose hypometabolism in the depressed state: a confirmation. Am J Psychiatry 1990;147(10): 1313–1317. 162. Hurwitz TA, Clark C, Murphy E, Klonoff H, Martin WR, Pate BD. Regional cerebral glucose metabolism in major depressive disorder. Can J Psychiatry 1990;35(8):684–688. 163. Mayberg HS, Brannan SK, Mahurin RK, et al. Cingulate function in depression: a potential predictor of treatment response. Neuroreport 1997;8(4):1057–1061. 164. Drevets WC, Videen TO, Price JL, Preskorn SH, Carmichael ST, Raichle ME. A functional anatomical study of unipolar depression. J Neurosci 1992;12(9):3628–3641. 165. Abercrombie HC, Schaefer SM, Larson CL, et al. Metabolic rate in the right amygdala predicts negative affect in depressed patients. Neuroreport 1998;9(14):3301–3307. 166. Drevets WC, Price JL, Bardgett ME, Reich T, Todd RD, Raichle ME. Glucose metabolism in the amygdala in depression: relationship to diagnostic subtype and plasma cortisol levels. Pharmacol Biochem Behav 2002;71(3):431–447. 167. Smith GS, Reynolds CF 3rd, Pollock B, et al. Cerebral glucose metabolic response to combined total sleep deprivation and antidepressant treatment in geriatric depression. Am J Psychiatry 1999;156(5): 683–689. 168. Wu JC, Gillin JC, Buchsbaum MS, Hershey T, Johnson JC, Bunney WE Jr. Effect of sleep deprivation on brain metabolism of depressed patients. Am J Psychiatry 1992;149(4):538–543. 169. Biver F, Goldman S, Delvenne V, et al. Frontal and parietal metabolic disturbances in unipolar depression. Biol Psychiatry 1994;36(6):381– 388. 170. Bench CJ, Friston KJ, Brown RG, Frackowiak RS, Dolan RJ. Regional cerebral blood flow in depression measured by positron emission tomography: the relationship with clinical dimensions. Psychol Med 1993;23(3): 579–590.

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20 Epilepsy Nicolaas I. Bohnen and James M. Mountz

PET for Functional and Neurochemical Imaging Positron emission tomography (PET) can be used to perform neurochemical and functional brain imaging studies. First, neurochemical imaging studies allow assessment of the regional distribution and quantitative measurement of neurotransmitters, enzymes, or receptors in the living brain. Benzodiazepine receptor binding scans are an example of neurochemical receptor studies that are used in the evaluation of children with epilepsy. Second, functional brain imaging studies can measure regional cerebral blood flow (rCBF) or glucose metabolism. These studies may be performed in the resting state when the child is not having seizures (interictal) or at the time of a seizure (ictal study). Seizure activation of the brain is accompanied by increases in rCBF and glucose consumption. Interictal fluorodeoxyglucose (FDG)-PET studies are most commonly performed in the clinical PET imaging evaluation of children with epilepsy at the present time. Although technically more challenging, ictal FDG- or rCBF-PET studies may be performed when children have frequent or predictable seizures.

Imaging for Presurgical Workup Epileptic syndromes are classified as generalized and partial types of seizures. Primary generalized epilepsy is associated with diffuse and bilateral epileptiform discharges on an electroencephalogram (EEG) without evidence of focal brain lesions. In contrast, partial epilepsy is thought to arise from a focal gray matter lesion (localization-related epilepsy). Partial-onset seizures may remain partial or may secondarily generalize. Medically refractory epilepsy is defined by seizure syndromes that are not effectively controlled by antiepileptic drugs. The management of medically refractory partial epilepsy has been revolutionized by neurosurgical techniques aimed at the resection of the epileptogenic brain focus. Therefore, precise seizure localization is the primary objective of the presurgical workup. Electroencephalogram 361

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monitoring and structural brain imaging using magnetic resonance imaging (MRI) are part of the standard workup of epilepsy patients undergoing presurgical evaluation. Functional imaging studies, such as FDG-PET, can provide additional localizing information in patients with nonlocalizing surface ictal EEG and can reduce the number of patients requiring intracranial EEG studies (1). Even when intracranial EEG is required, FDG-PET can be helpful in guiding placement of subdural grids or depth electrodes prior to surgical ablative therapy. Obtaining a FDG-PET scan is strongly recommended before performing intracranial EEG because prior depth electrode insertion can cause small hypometabolic regions that may lead to false-positive PET interpretations (2). The FDG-PET scan in the routine clinical setting is usually interpreted in a qualitative analysis by physicians experienced in the normal cerebral distribution of the tracer in the brain. Figure 20.1 shows a normal FDG-PET brain scan of a 16-year-old girl. It was performed on the Siemens (CTI PET Systems, Knoxville, TN)

A Figure 20.1. Normal FDG-PET scan in 16–year-old girl. The normal mild asymmetry in metabolism typically seen in the temporal lobe is illustrated, as well as the normal degree of apparent reduction in metabolism in the anterior and mesial temporal lobe regions. A: Normal MRI scan. B: Normal FDGPET scan.

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HR+ dedicated brain PET scanner. After the intravenous injection of 7.2 mCi of fluorine-18 (18F)-FDG, the patient waited on a comfortable recliner in a dimly lit, quiet room for approximately 30 minutes to allow for tracer incorporation into the brain. The figure illustrates the typical pattern of FDG uptake in the brain of a child. It has been previously reported that there is increased metabolic activity in the anterior cingulate cortex and thalamus in children (3). Figure 20.1 also illustrates the importance of using symmetry or other semiqualitative methods to establish the presence of abnormally reduced metabolism in the temporal lobes, because there is a variability of symmetrical uptake of approximately 15% in this location (4). The PET scan should be interpreted as being abnormal if there is a definite focal area of reduced FDG uptake identified during the interictal state. It is also highly recommended that the FDG-PET scan be reviewed with full information available including the current MRI scan, clinical history, neurologic examination, seizure semiology, and EEG results.

B Figure 20.1. Continued.

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Regional Glucose Hypometabolism and Epileptogenic Focus The use of FDG-PET in clinical epilepsy emerged from early observations of regionally reduced cortical glucose metabolism at the site of the epileptogenic focus (5). It should be noted that FDG-PET may show more widespread hypometabolism than suspected on the basis of the scalp-recorded EEG (1). The pathophysiology of interictal cortical hypometabolism in partial epilepsy is incompletely understood. Areas of interictal hypometabolism in epileptogenic cortex appear to be partially uncoupled from blood flow with metabolic reductions being greater relative to flow (6). Although there are significant correlations between hippocampal volume and inferior mesial and lateral temporal lobe cerebral metabolic rates in patients with temporal lobe epilepsy (7), hippocampal neuronal loss cannot fully account for the regional interictal hypometabolism of temporal lobe epilepsy (8). Children with new onset of seizures are less likely to have hypometabolism (9). Therefore, it is uncertain whether hypometabolism reflects the effects of repeated seizures on the brain, the underlying pathologic process, or an initial insult such as early status epilepticus (9). It is possible that synaptic mechanisms rather than cell loss may contribute to the observed hypometabolism (10).

Ictal SPECT Combined with Interictal FDG Single photon emission computed tomography (SPECT) is a nuclear medicine imaging method that facilitates the measurement of rCBF (11). Its utility is based on the fact that partial seizures are associated with an increase in rCBF (12). In ictal SPECT, a photon-emitting radiotracer [usually technetium-99m (99mTc)-hexamethylproleneamineoxime (HMPAO) or 99mTc-ethylcysteinate dimer (ECD)] is injected intravenously at the onset of a seizure and the subject is scanned when stable using a rotating gamma camera to obtain SPECT images. This provides a three-dimensional image of the distribution of the radiotracer during the seizure, for the radiotracer accumulates and remains “fixed” in different areas of the brain proportional to the cerebral perfusion to those regions at the time of injection. In partial seizures, the increased blood flow closely corresponds with the site of seizure origin. The interpretation of ictal rCBF-SPECT has several potential limitations. Extratemporal seizures are often associated with multiple areas of increased rCBF that may be due to seizure propagation or to individual variability in the baseline rCBF patterns of tracer uptake (13–15). Also, if the epileptogenic zone is hypoperfused at baseline (interictal), the ictal increase in tracer uptake may be obscured despite relative hyperperfusion (15,16). These factors have led to the widespread but not universal practice of combining an ictal with an interictal study (13,15,16). Typically, qualitative comparison of the ictal and interictal studies is undertaken when both are available; otherwise, qualitative or semi-

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Figure 20.2. A 9–year-old, right-handed boy with history of intractable partial epilepsy. A: MRI coronal sections through the mesial temporal lobe region show left mesial temporal lobe sclerosis with villous atrophy. B: Transverse sections from a FDG-PET scan show left temporal lobe hypometabolism with greatest reduction in the left mesial temporal lobe. C: Transverse interictal regional cerebral blood flow (rCBF)-SPECT (top two rows) compared with ictal rCBF-SPECT (bottom two rows) shows increased blood flow to the lateral temporal lobe region during ictus. D: Coronal interictal rCBF-SPECT of the same scan as shown in C (top two rows) compared with ictal rCBF-SPECT (bottom two rows) shows increased blood flow to the lateral temporal lobe region during ictus.

quantitative side-to-side comparison of the ictal study alone is performed. More recently it has been shown that the accuracy of this method may be enhanced by subtraction of the interictal from the ictal SPECT and then co-registration of the resulting images onto MRI (15). Ictal SPECT can corroborate the findings on interictal FDG, as shown in Figure 20.2. However, due to late propagation and cross-hemispheric electrocortical activation, the findings on ictal SPECT must be carefully interpreted. This difficulty with ictal SPECT is illustrated in a 9-yearold, right-handed boy with history of intractable partial epilepsy. Seizure onset was in the first few months of life. The EEG showed left temporal slowing as well as left sharp waves. An MRI scan showed left

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medial temporal sclerosis with villous atrophy. The FDG-PET scan showed left medial temporal hypometabolism. However, the ictal SPECT showed an increase in left lateral temporal lobe perfusion. Thus, although ictal SPECT correctly lateralized the epileptogenic focus to the correct lobe of the brain, only interictal FDG-PET localized the true epileptogenic focus to the left mesial temporal lobe.

Interictal FDG-PET Studies in Temporal Lobe Epilepsy (TLE) Mesial temporal lobe epilepsy is commonly associated with hippocampal sclerosis. Fluorodeoxyglucose-PET has high sensitivity in detecting temporal hypometabolic foci and can be visualized as a region of reduced metabolism that, when compared to the normal temporal lobe, may show a significant asymmetry in FDG uptake (4). Figure 20.3 illustrates concordance between abnormalities on MRI and FDG-PET in a 16-year-old boy with temporal lobe epilepsy. The MRI shows abnormal high signal intensity in the right hippocampal region. The FDG-PET shows a corresponding area of focal reduction of FDG uptake in the right hippocampal region. Fluorodeoxyglucose-PET is most useful for those patients with TLE who have equivocal or no structural MRI abnormalities to provide the necessary lateralization information (7,17). Although most patients with TLE will have the findings of hippocampal sclerosis on a high resolution MRI, a significant minority of patients with electroclinically well-lateralized temporal lobe seizures have no evidence of sclerosis on

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Figure 20.3. Right mesial temporal lobe sclerosis in a 16–year-old boy. The MRI-PET fusion image illustrates that the reduction in FDG corresponds to the region of MRI increase in signal intensity in the right mesial temporal lobe (hippocampal region).

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MRI (18). Figure 20.4 illustrates a normal MRI scan and an abnormal FDG-PET scan in a 15-year-old boy with intractable complex partial seizures. He averaged about one to two complex partial seizures a month and two to three simple partial seizures per day. His surface EEG showed ictal discharges from the right frontotemporal region. The MRI and interictal rCBF-SPECT studies were normal. An interictal FDG-PET showed right temporal hypometabolism involving medial and anterior aspects of the right temporal lobe. It should be noted that false lateralization is rare but may occur in FDG-PET studies of temporal lobe epilepsy. For example, unrecognized epileptic activity can make the contralateral temporal lobe appear spuriously depressed (2). Furthermore, normal right-to-left asymmetry between temporal lobes should not be interpreted as pathologic hypometabolism. Although FDG-PET images can be analyzed visually, additional information can be obtained by semiquantitative analysis, such as left-to-right asymmetry indices. Semiquantitative analysis using the asymmetry index is generally considered significant when a difference of 15% or greater exists between the affected and contralateral sides (19). Quantitative asymmetry indices should reduce potential error due to misinterpreting these normal left-to-right variations (20). Registration programs can be used to align structural MRI and PET for more precise anatomic localization of the hypometabolic area. Although regional hypometabolism is typically present in the temporal lobe ipsilateral to EEG seizure onset, other brain regions may also show patterns of glucose hypometabolism. For example, an FDG-PET study of patients with temporal lobe epilepsy demonstrated hypometabolic regions ipsilateral to seizure onset that included lateral temporal (in 78% of patients), mesial temporal (70%), thalamic (63%), basal ganglia (41%), frontal (30%), parietal (26%), and occipital (4%) regions (21). In pure TLE, however, the extratemporal hypometabolic regions rarely show epileptiform activity on EEG but may be affected by rapid seizure propagation (21). Cerebellar hypometabolism may be ipsilateral, contralateral, or bilateral, depending on the distribution and spread of ictal activity and possible effects of phenytoin therapy (2,22). Bilateral cerebellar hypometabolism, which often is present, cannot be fully explained by the effects of phenytoin (22). Unilateral temporal hypometabolism predicts good surgical outcome from temporal lobectomy. The greater the metabolic asymmetry, the greater the chance of becoming seizure-free (2). Bilateral temporal hypometabolism may represent a relative contraindication for surgery (2). Similarly, thalamic asymmetry on FDGPET is a strong predictor of surgical outcome; hypometabolism in the thalamus contralateral to the presumed EEG focus almost invariably predicts poor surgical outcome (23).

FDG-PET Imaging in Extratemporal Epilepsy The localization of epileptic foci in patients who have intractable extratemporal epilepsy remains a major diagnostic challenge in the

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A Figure 20.4. A 15–year-old boy with intractable complex partial seizures. A: Normal MRI scan. B: Interictal FDG-PET shows right temporal hypometabolism in the hippocampal region.

presurgical evaluation of children with epilepsy. The most common underlying pathology in extratemporal neocortical epilepsy is microscopic focal cortical dysplasia, which cannot be readily detected by current MRI techniques (24). Fluorodeoxyglucose-PET may not be as valuable in the evaluation of patients with extratemporal seizures, such as frontal lobe epilepsy, because of limited sensitivity (20,25). Areas of hypometabolism in frontal lobe epilepsy have been found to be focal, regional, or hemispheric (26). Interictal hypometabolism may be uncommon in the absence of co-localized structural imaging abnormality in frontal lobe epilepsy (27). Furthermore, large zones of extrafrontal, particularly temporal, hypometabolism are commonly observed ipsilateral to frontal hypometabolism in frontal lobe epilepsies (27). Figure 20.5 illustrates this limitation on the localization capability of interictal FDGPET in extratemporal lobe epilepsy in a 14-year-old girl with intractable epilepsy. The patient had one to two brief seizures per day. Video-EEG monitoring was nonlocalizing. The MRI scan was normal. Ictal 99mTcHMPAO showed focal intense right frontal lobe hyperperfusion. Interictal FDG-PET was nonlocalizing, but in retrospect, after review of the

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ictal rCBF study, showed subtle right frontal hypometabolism. In this case interictal FDG was confirmatory but by itself was not localizing. Recent data show that observer-independent automatic statistical brain mapping techniques may increase the usefulness of FDG-PET in patients with extratemporal lobe epilepsy (28). For example, a study using an automated brain mapping method found significantly higher sensitivity in detecting the epileptogenic focus (67%) than visual analysis (19% to 38%) in patients with extratemporal epilepsy (29). Hypometabolic regions in partial epilepsies of neocortical origin have been usually associated with structural imaging abnormalities (25). Therefore, PET data should always be interpreted in the context of high-quality anatomic MRI, providing a structuralfunctional correlation. The importance of precise localization using an an automated registration mapping method is illustrated in Figure 20.6,

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Figure 20.5. A 14–year-old girl with a history of intractable epilepsy with seizure frequency as one to two seizures per day. MRI coronal sections are normal (left upper quadrant). FDG-PET shows normal variability in metabolic uptake with no convincing areas of metabolic reduction that are diagnostic for the epileptogenic focus (right upper quadrant). Ictal technetium-99m (99mTc)-hexamethylproleneamineoxime (HMPAO) SPECT in coronal section (top) demonstrates a region of focal intense blood flow in the right medial frontal lobe compared with co-registered coronal sections from the interictal FDG-PET scan. In retrospect, a region of hypometabolism is detectable (left lower quadrant). Co-registered MRI, ictal SPECT, and FDG-PET images show the MRI is normal in the location of intense hyperemia on ictal SPECT, in the same area retrospectively showing hypometabolism on PET (right upper quadrant).

䉴 Figure 20.6. A 15–year-old boy with generalized tonic-clonic seizures from a right parieto-occipital cavernous venous angioma. A: MRI shows right parietooccipital cavernous venous angioma. B: FDG-PET scan shows reduced metabolism in the area of the cavernous venous angioma. C: Ictal SPECT transverse section (bottom) shows increased blood flow to the right parietal lobe in the location of the angioma. Interictal SPECT (top) shows reduced blood flow corresponding to the location of the angioma. D: Ictal SPECT sagittal section (bottom) shows increased blood flow to the right parietal lobe in the location anterior to the angioma. Interictal SPECT (top) shows reduced blood flow corresponding to the location of the angioma. E: Statistical pixel analysis map in transverse section of significant ictal rCBF greater than interictal rCBF (yellow) or less that interictal rCBF (blue). Map shows significant ictal associated hyperemia in the region of the angioma. F: Statistical pixel analysis map in sagittal section of significant ictal rCBF greater than interictal rCBF (yellow) or less that interictal rCBF (blue). Map shows significant ictal associate hyperemia anterior to the angioma. (See color insert, parts E and F only.)

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see color insert, by the example of a 15-year-old, right-handed boy undergoing evaluation for a generalized tonic-clonic seizure disorder caused by a right parietooccipital cavernous venous angioma. The EEG showed right parieto-occipital focal slow and sharp waves. The MRI showed right parieto-occipital cavernous venous angioma with evidence of bleeding. The FDG-PET scan showed reduced metabolism in the area of the cavernous venous angioma. An ictal SPECT showed increased uptake in the right parietal lobe, anterior and medial to the area of reduction of blood flow in right parietal lobe caused by the angioma. The patient underwent electrocorticography and mapping of the lesion for subsequent resection of the lesion and surrounding epileptogenic area. On electrocorticography and intraoperative mapping, the area of increased epileptogenesis was found to correlate with the findings of ictal SPECT. Interictal FDG-PET studies have limited usefulness in the presence of multiple hypometabolic regions in patients with multifocal brain syndromes, such as in children with tuberous sclerosis. Such children with multifocal lesions represent a special challenge during presurgical evaluation. The goal of functional imaging in these cases is to identify the epileptogenic lesions and differentiate them from nonepileptogenic ones. In this context, ictal rCBF-SPECT may have useful clinical applications but may be technically challenging when seizures are short, as is particularly common in frontal lobe epilepsy and in children who have infantile spasms that are associated with multifocal cortical dysplasia (30). Figure 20.7 shows such a case in a 1-year-old boy with tuberous sclerosis. Several lesions appeared anatomically abnormal on the CT portion of the PET-CT scan. These areas also showed reduced FDG uptake on PET. Ictal SPECT was able to identify the dominant area of presumed epileptogenesis associated with a large tuber in the right frontal lobe.

䉴 Figure 20.7. A 1–year-old boy with tuberous sclerosis underwent a PET– computed tomography (CT) scan as well as ictal and interictal rCBF-SPECT. A: CT portion of PET-CT scan showing the tubers. B: FDG-PET portion of PETCT scan showing reduced metabolism in the multiple areas of the tubers. C: PET-CT fusion image showing that the areas of decreased metabolism correspond to the numerous tuber abnormalities identified on the CT scan. D: FDGPET scan coronal sections showing reduced metabolism in multiple areas of the tubers. E: Ictal rCBF-SPECT coronal section (bottom) showing intense hyperemia corresponding to the large tuber in the right frontal lobe. Interictal rCBF-SPECT does not show blood flow reduction to the degree of metabolic reduction identified on interictal PET.

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FDG-PET Studies of Children with Infantile Spasms (West Syndrome) An infantile spasm is an epileptic syndrome that begins in early infancy in which children have tonic and myoclonic seizures, arrhythmia on EEG, and development arrest. Among patients with infantile spasms, FDG-PET studies suggest that the spasms are the result of secondary generalization from cortical foci and that maturational factors result in the recruitment of basal ganglia and brainstem serotonin mechanisms that lead to secondary generalization and the unique semiology of the spasms (31,32). Most infants who are diagnosed with “cryptogenic” spasms have focal or multifocal cortical regions of decreased (or occasionally increased) glucose metabolic activity on PET that are often consistent with areas of cortical dysplasia missed by MRI (31,33). When a single region of abnormal glucose hypometabolism is apparent on PET and corresponds to the EEG focus, and the seizures are intractable, surgical removal of the PET focus results in seizure control and in complete or partial reversal of the associated developmental delay (30). When the pattern of glucose hypometabolism is generalized and symmetric, a lesional cause is not likely, and neurometabolic or neurogenetic disorders should be considered when further evaluating the child

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(30). Results of serial FDG-PET imaging have shown that when PET after the initial treatment shows no abnormalities, even though the first PET shows hypometabolism, infants with cryptogenic West syndrome may have a favorable developmental or seizure outcome (34).

FDG-PET Studies in Lennox-Gastaut Syndrome Lennox-Gastaut syndrome is a childhood epileptic encephalopathy characterized by an electroclinical triad of generalized slow spike wave activity in the EEG, multiple types of epileptic seizures, and slow mental development. It is usually subdivided into symptomatic and cryptogenic types, the latter accounting for at least one fourth of all patients. Symptomatic cases are due to diverse cerebral conditions, which are usually bilateral, diffuse, or multifocal, involving cerebral gray matter (35). Fluorodeoxyglucose-PET studies have shown that Lennox-Gastaut syndrome can be classified into four predominant subtypes, each with a distinct metabolic pattern: unilateral focal hypometabolism, unilateral diffuse hypometabolism, bilateral diffuse hypometabolism, and normal (36). Patients who have the unilateral focal and unilateral diffuse patterns may be considered for cortical resection provided that there is concordance between FDG-PET and ictal EEG findings (30).

Interictal and Ictal PET Studies Interictal 15O-H2O rCBF-PET Studies It should be noted that interictal oxygen-15 (15O)-H2O rCBF-PET studies, when compared to FDG-PET studies, have reduced sensitivity in localizing epileptogenic zones and sometimes may be false lateralizing (37). Furthermore, rCBF-PET scans are noisier than FDG-PET, which may increase partial volume effects and make detection of a hypoperfused area more difficult. Therefore, interictal rCBF-PET studies are unreliable markers for epileptic foci and should not be used in the presurgical evaluation of patients with epilepsy (6). Ictal PET Although not always practical, FDG-PET can also be used for ictal studies in patients who have frequent seizures (38). It should be noted that FDG-PET may be less accurate for ictal compared to interictal glucose metabolic measurements because seizures may alter the “lumped constant,” which describes the relationship between FDG and its physiologic substrate glucose (2). Furthermore, a typical seizure is much shorter than the average 30-minute FDG uptake period. Therefore, an “ictal” scan may include interictal, ictal, and postictal metabolic changes with combinations of hypermetabolic and hypometabolic regions (2). 15O-H2O PET imaging has been used to study quantitative alterations in rCBF accompanying seizures induced by pentylenetetrazole (39). Patients with generalized tonic-clonic seizures demonstrated asymmetric flow increases. One patient with a complex partial seizure

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demonstrated 70% to 80% increases in bitemporal flow. Thalamic flow increased during both complex partial and generalized seizures, indicating the importance of this subcortical structure during ictal activation (39). Factors That May Affect Interpretation of Interictal and Ictal FDG-PET Studies A number of other factors need to be considered when interpreting brain PET images of children with epilepsy. It should be realized that brain glucose metabolic or blood flow PET images are functional in nature. For example, when a child is moving or talking around the time of injection, increased activity in specific brain regions, like the basal ganglia, motor cortex, or language centers, may be present. Metabolic activity in the visual cortex was increased in subjects studied with their eyes open when compared to a baseline of subjects studied with their eyes closed (40). Therefore, knowledge of the clinical or behavioral state of the patient at the time of the injection and study is critical for proper image interpretation. Positron emission tomography in children often requires sedation. An FDG-PET study of propofol sedation in children found significant hypometabolism in the medial parieto-occipital cortex bilaterally, including the lingual gyrus, cuneus, and middle occipital gyrus (41). The bilateral parieto-occipital hypometabolism is likely to be a sedation-specific effect and should be taken into account when evaluating cerebral FDG-PET scans in sedated children. Diazepam sedation has been found to reduce cerebral glucose metabolism globally by about 20% (42). A study by Wang et al. (43) found that lorazepam significantly decreased whole-brain metabolism over 10%. However, regional effects of lorazepam were largest in the thalamus and occipital cortex (about 20% reduction). Similarly, antiepileptic drugs have been found to reduce glucose metabolism and rCBF. Studies on valproate have shown global FDG (about 9% to 10%) and global CBF (about 15%) reductions with greatest regional reductions in the thalamus (44). Phenytoin has been found to cause an average reduction of cerebral glucose metabolism by 13% (45). Cerebellar metabolism may also be reduced by phenytoin, although the effect of the drug is probably less than that due to early onset of uncontrolled epilepsy (22,46). Studies on the barbiturate phenobarbital and cerebral glucose metabolism have shown very prominent global reductions of about 37% (47).

Emerging Clinical Applications of Neurochemical PET Imaging The inhibitory neurotransmitter g-aminobutyric acid (GABA) has anticonvulsant properties. Benzodiazepine receptor ligands, such as carbon-11 (11C)-flumazenil (FMZ), have been used to study the regional cerebral distribution of benzodiazepine receptor binding sites that are related to GABAA receptors. The high density of GABAA receptors in the normal hippocampus accounts for the high sensitivity of FMZ-PET

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to detect even mild decreases in binding that are consistent with hippocampal sclerosis in TLE. Where available, FMZ-PET provides a useful alternative for FDG-PET in the evaluation of children with epilepsy. A regional decrease in benzodiazepine receptor binding has been associated with the presence of a possible epileptogenic focus. Unilaterally decreased temporal FMZ binding can also help to lateralize the epileptic focus in patients who have TLE that is associated with bilateral temporal hypometabolism on FDG-PET (30). When compared to FDG studies, FMZ-PET studies have been reported to demonstrate less extensive cortical involvement. For example, a study comparing FDG and FMZ-PET imaging in patients with temporal lobe epilepsy found a wide range of mesial temporal, lateral temporal, and thalamic glucose hypometabolism ipsilateral to ictal EEG changes as well as extratemporal hypometabolism. In contrast, each patient demonstrated decreased benzodiazepine-receptor binding in the ipsilateral anterior mesial temporal region, without neocortical changes. Thus, interictal metabolic dysfunction can be variable and usually is extensive in temporal lobe epilepsy, whereas decreased central benzodiazepinereceptor density appears to be more restricted to mesial temporal areas (48). Similar benzodiazepine receptor findings have been reported for patients with extratemporal lobe seizures caused by focal cortical dysplasia (49). Unlike the more widespread glucose hypometabolic patterns, benzodiazepine receptor changes may reflect localized neuronal loss that is more specific to the epileptogenic zone (48). Therefore, FMZ imaging may be useful in the presurgical evaluation of children with epilepsy. However, focal increases of benzodiazepine receptor binding have also been reported in the temporal lobe as well as extratemporal sites in patients with temporal lobe epilepsy when statistical brain mapping analysis is performed (50). This may lead to false-localizing information when attention is paid only to areas of decreased uptake. The development of radioligands that are specific for excitatory amino acid and selected opioid receptor subtypes, such as 11Ccarfentanil for mu-opiate receptors, may help to better explore the pathophysiology of epileptic syndromes. Another promising direction in the development of new PET tracers for epilepsy is to target serotonergic neurotransmission. A novel tracer, a-11C-methyl-L-tryptophan (AMT), which accumulates in epileptic foci in the interictal state, can be a useful approach to identify epileptogenic sites in children with multifocal brain lesions (30,51). This radiotracer may also be useful in identifying nonresected epileptic cortex in young patients with a previously failed neocortical epilepsy surgery (52).

Conclusion The use of FDG-PET in clinical epilepsy emerged from early observations of regionally reduced cortical glucose metabolism at the site of the epileptogenic focus. Fluorodeoxyglucose is the most commonly used PET radiotracer in the diagnostic and presurgical evaluation of

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children with epilepsy at the present time. Measurement of receptors or neurotransmitter metabolism is a unique ability of PET that has not achieved its full potential in the study of pediatric epilepsy. For example, PET measures of central benzodiazepine receptor binding and serotonin synthesis may have increasing clinical applications in the presurgical evaluation of children with localization-related epilepsy. It is anticipated that the use of such tracers will further enhance the clinical yield of PET in the diagnostic workup and presurgical evaluation of children with medically intractable epilepsy and will further improve our understanding of the pathophysiology of pediatric epilepsy.

References 1. Theodore WH, Newmark ME, Sato S, et al. [18F]fluorodeoxyglucose positron emission tomography in refractory complex partial seizures. Ann Neurol 1983;14:429–437. 2. Theodore WH. Positron emission tomography in the evaluation of seizure disorders. Neurosci News 1998;1:18–22. 3. Van Bogaert P, Wikler D, Damhaut P, Szliwowski HB, Goldman S. Regional changes in glucose metabolism during brain development from the age of 6 years. Neuroimage 1998;8:62–68. 4. Henry TR, Van Heertum RL. Positron emission tomography and single photon emission computed tomography in epilepsy care. Semin Nucl Med 2003;33:88–104. 5. Kuhl DE, Engel J, Phelps ME, Selin C. Epileptic patterns of local cerebral metabolism and perfusion in humans determined by emission computed tomography of 18FDG and 13NH3. Ann Neurol 1980;8:348–360. 6. Gaillard WD, Fazilat S, White S, et al. Interictal metabolism and blood flow are uncoupled in temporal lobe cortex of patients with complex partial epilepsy. Neurology 1995;45:1841–1847. 7. Gaillard WD, Bhatia S, Bookheimer SY, Fazilat S, Sato S, Theodore WH. FDG-PET and volumetric MRI in the evaluation of patients with partial epilepsy. Neurology 1995;45:123–126. 8. Henry TR, Babb TL, Engel J Jr, Mazziotta JC, Phelps ME, Crandall PH. Hippocampal neuronal loss and regional hypometabolism in temporal lobe epilepsy. Ann Neurol 1994;36:925–927. 9. Theodore WH. Cerebral blood flow and glucose metabolism in human epilepsy. In: Advances in Neurology, vol. 79. Philadelphia: Lippincott Williams & Wilkins, 1999:873–881. 10. Hajek M, Wieser HG, Khan N, et al. Preoperative and postoperative glucose consumption in mesiobasal and lateral temporal lobe epilepsy. Neurology 1994;44:2125–2132. 11. Mountz JM, Deutsch G, Kuzniecky R, Rosenfeld SS. Brain SPECT: 1994 Update. In: Freeman LM, ed. Nuclear Medicine Annual 1994. New York: Raven Press, 1994:1–54. 12. Horsely V. An address on the origin and seat of epileptic disturbance. Br Med J 1892;1:693–696. 13. Marks DA, Katz A, Hoffer P, Spencer SS. Localization of extratemporal epileptic foci during ictal single photon emission computed tomography. Ann Neurol 1992;31:250–255.

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N.I. Bohnen and J.M. Mountz 33. Chugani HT, Shewmon DA, Shields WD, et al. Surgery for intractable infantile spasms: neuroimaging perspectives. Epilepsia 1993;34:764–771. 34. Itomi K, Okumura A, Negoro T, et al. Prognostic value of positron emission tomography in cryptogenic West syndrome. Dev Med Child Neurol 2002;44:107–111. 35. Markand ON. Lennox-Gastaut syndrome (childhood epileptic encephalopathy). J Clin Neurophysiol 2003;20:426–441. 36. Chugani HT, Mazziotta JC, Engel JJ, Phelps ME. The Lennox-Gastaut syndrome: metabolic subtypes determined by 2–deoxy-2[18F]fluoro-D-glucose positron emission tomography. Ann Neurol 1987;21:4–13. 37. Leiderman DB, Balish M, Sato S, et al. Comparison of PET measurements of cerebral blood flow and glucose metabolism for the localization of human epileptic foci. Epilepsy Res 1992;13:153–157. 38. Meltzer CC, Adelson PD, Brenner RP, et al. Planned ictal FDG PET imaging for localization of extratemporal epileptic foci. Epilepsia 2000;41: 193–200. 39. Theodore WH, Balish M, Leiderman D, Bromfield E, Sato S, Herscovitch P. Effect of seizures on cerebral blood flow measured with 15O-H2O and positron emission tomography. Epilepsia 1996;37:796–802. 40. Mazziotta JC, Phelps ME, Carson RE, Kuhl DE. Tomographic mapping of human cerebral metabolism: sensory deprivation. Ann Neurol 1982;12: 435–444. 41. Juengling FD, Kassubek J, Martens-Le Bouar H, et al. Cerebral regional hypometabolism caused by propofol-induced sedation in children with severe myoclonic epilepsy: a study using fluorodeoxyglucose positron emission tomography and statistical parametric mapping. Neurosci Lett 2002;335:79–82. 42. Foster NL, VanDerSpek AF, Aldrich MS, et al. The effect of diazepam sedation on cerebral glucose metabolism in Alzheimer’s disease as measured using positron emission tomography. J Cereb Blood Flow Metab 1987;7:415–420. 43. Wang GJ, Volkow ND, Overall J, et al. Reproducibility of regional brain metabolic responses to lorazepam. J Nucl Med 1996;37:1609–1613. 44. Gaillard WD, Zeffiro T, Fazilat S, DeCarli C, Theodore WH. Effect of valproate on cerebral metabolism and blood flow: an 18F-2–deoxyglucose and 15O water positron emission tomography study. Epilepsia 1996;37: 515–521. 45. Theodore WH, Bairamian D, Newmark ME, et al. Effect of phenytoin on human cerebral glucose metabolism. J Cereb Blood Flow Metab 1986;6: 315–320. 46. Seitz RJ, Piel S, Arnold S, et al. Cerebellar hypometabolism in focal epilepsy is related to age of onset and drug intoxication. Epilepsia 1996;37:1194– 1199. 47. Theodore WH. Antiepileptic drugs and cerebral glucose metabolism. Epilepsia 1988;29(suppl 2):S48–S55. 48. Henry TR, Frey KA, Sackellares JC, et al. In vivo cerebral metabolism and central benzodiazepine-receptor binding in temporal lobe epilepsy. Neurology 1993;43:1998–2006. 49. Arnold S, Berthele A, Drzezga A, et al. Reduction of benzodiazepine receptor binding is related to the seizure onset zone in extratemporal focal cortical dysplasia. Epilepsia 2000;41:818–824. 50. Koepp MJ, Hammers A, Labbe C, Woermann FG, Brooks DJ, Duncan JS. 11 C-flumazenil PET in patients with refractory temporal lobe epilepsy and normal MRI. Neurology 2000;54:332–339.

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21 Neurotransmitter Imaging Alan J. Fischman and Rajendra D. Badgaiyan

In recent years, investigators have used a variety of techniques to study human neurotransmission in health and disease. One of the most promising of these techniques is molecular or neurotransmitter imaging, which, despite being an emerging technique, has made significant contribution to our understanding of human neurotransmission (1,2). Molecular imaging has been used by numerous investigators to establish maps of the functional anatomy of neuroreceptorradioligand interaction (3,4). Recently, it has been applied to the detection of dynamic changes in neurotransmitter activity induced by behavioral, cognitive, or pharmacologic interventions (5–12). This chapter includes a brief outline of the basic concepts of neurotransmitter imaging, important information acquired using this technique, and a discussion of dynamic receptor imaging.

Basic Concepts Neurotransmitter imaging techniques exploit the competition between an endogenous neurotransmitter and a radiolabeled ligand (usually an agonist or antagonist of the neurotransmitter) that binds to the target receptor. With this technique, the concentration of the radiolabeled ligand (administered intravenously or orally) is measured at different brain regions, using positron emission tomography (PET) or single photon emission computed tomography (SPECT). These measurements provide information concerning active receptors and facilitate estimation of changes induced by a challenge (13). Because the reliability and accuracy of the estimation depend on the kinetics of receptor-ligand interaction, selection of an appropriate ligand is critical for success (14). An ideal ligand has high affinity and selectivity for the target receptor, is permeable across the blood–brain barrier, has low nonspecific binding, and is not metabolized in brain tissue (15). Another factor that affects the accuracy of measurement is the proportion of administered ligand that actually binds to the target receptor (specific binding). 385

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Tomographic methods measure the concentration of ligand in areas of interest; this concentration includes ligand that is bound to the receptor, that is present in the extracellular fluid, or that is bound to the tissue or plasma proteins (nonspecific binding). Because only specific binding provides information concerning neurotransmission, nonspecific binding must be estimated and excluded from the ligand concentration detected by the camera. The exclusion of nonspecific binding is done by applying a correction to the total concentration. Because this correction is calculated using models that provide only an approximate estimation of the amount of nonspecifically bound ligand, measurements of specific binding are more accurate if nonspecific binding is low (16–18). A number of models have been developed for the estimation of specific binding. The most commonly used model (three-compartment model) assumes that in the brain, a ligand is distributed in three compartments (Fig. 21.1): the plasma compartment, the nondisplaceable compartment (free and nonspecifically bound ligand), and the receptor compartment (3,4). The concentration of ligand in these compartments changes if there is a positive gradient between the blood and tissue concentration. It eventually approaches equilibrium, and a steady-state volume of distribution is achieved. In this state, the ligand concentration in different compartments remains constant (17). In this model, the relationship between the concentration of specifically bound ligand at steady state (B), the maximum number of receptors (Bmax), the concentration of free ligand (F), and the dissociation rate constant of the ligand (KD) can be defined using the Michaelis-Menton equation (19): B=

Bmax ◊ F KD + F

If a tracer dose of ligand is administered (as is the usual practice), the value of F is very small (as compared to that of KD) and can be disregarded in the denominator of this formula. Thus the specific binding of a tracer can be expressed as B=

Bmax ◊ F KD

Conventionally, the specific binding is expressed in terms of binding potential (BP), which indicates the capacity of a brain region for specific binding. Most investigators define BP as the steady state ratio

K1 Plasma compartment

K3 Nondisplaceable compartment

K2

Receptor compartment K4

Figure 21.1. Schematic diagram of the compartmental model used to analyze PET and SPECT data in receptor imaging studies. K1, k2, k3, and k4 represent the rate constants of the ligand movement between compartments.

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of the specifically bound (B) to free ligand (F). It is clear from the above equation that this ratio is equal to the ratio of Bmax and KD for tracers: BP =

B Bmax = F KD

Specific binding in a brain area can be measured by calculating the difference between ligand concentration in the area of interest and that in another area that is devoid of target receptor (or has a negligible number of receptors, e.g., cerebellum for dopamine receptor studies). The other variable, F, the free concentration of ligand in the brain cannot be measured directly. However, because ligands diffuse through the blood–brain barrier by passive diffusion, it can be assumed that, at equilibrium, the brain concentration equals the plasma concentration (20). This measurement of F, however, is not required if the objective of the study is to compare the BP in two groups of subjects. If the free ligand concentration is the same in the two groups, changes in specific binding will be proportional to the changes in BP. Further, by assuming that the free ligand concentration in the target and reference regions is the same at equilibrium, BP can be calculated by estimating the ratio of ligand concentration (C) in the target and reference region (BP = CTARG/CREF - 1). Theoretically, the ratio of ligand that enters the receptor compartment (k3) to that which leaves (k4) this compartment (BP = k3/k4) provides the best estimate of BP (3). If an intervention induces release of an endogenous neurotransmitter, the number of receptors occupied by the neurotransmitter will increase. Consequently, smaller number of receptors will be available for the radioligand, and BP will be reduced. The reduction, however, may not occur if the neurotransmitter modifies the behavior of ligandreceptor complex. Thus the BP of some ligands (e.g., 3H-spiperone) show a paradoxical increase after endogenous release of the neurotransmitter (21). This paradoxical behavior is caused by the neurotransmitter-promoted receptor internalization that results in trapping of the ligand in the cell (22). Neurotransmitter imaging has been used to study a variety of psychiatric and neurologic disorders to understand the nature of impairments of neurotransmission. Because dopaminergic and serotonergic ligands are most appropriate for molecular imaging, many studies have examined these systems. The following section provides a brief survey of the findings of these investigations.

Dopaminergic System Dopamine has been the most extensively studied neurotransmitter. The reason for the focus on dopaminergic transmission is its involvement in the pathogenesis of psychiatric and neurologic conditions. Availability of a number of dopamine ligands that are suitable for molecular imaging also contributed to the interest of investigators. Dopamine ligands have been developed from a host of agonists and antagonists

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of dopamine D1 and D2 receptors. Each of these ligands has different binding properties, and is therefore suitable for specific kinds of study. For example, the D2 receptor antagonist raclopride is the preferred ligand for studying striatal dopamine (Fig. 21.2), but it cannot be used to examine dopamine transmission in the extrastriatal brain areas because of its extremely low binding in areas where D2 receptor concentration are low (10,23). Newer D2 receptor ligands, 18F-fallypride, 11 C-FLB 457, and 11C-nemonapride have high affinity for extrastriatal D2 receptors, but their utility in detection of striatal dopamine has not yet been established (24–27). Most of the studies on dopamine neurotransmission have been conducted to understand the pathogenesis of psychiatric disorders. Schizophrenia has attracted many investigators because of the uncertainty concerning the role of the dopamine system in its pathogenesis (28). The findings of receptor imaging studies, however, are equivocal. Based on the ligand used, these studies have found either increased (29,30) or normal (31) density of D2 receptors in schizophrenia. Experiments that have used dopamine D1 receptor ligands have also reported contradictory findings. These studies have found normal, increased, or decreased density in the prefrontal cortex (32). Both increased and reduced densities are correlated with the degree of impairment in prefrontal functions (measured by tests of working memory and by Wisconsin card sorting tasks). The contradictory findings of these studies are possibly due to the diversity of ligands used. It is known that each ligand has different vulnerability to competition by endogenous dopamine (33,34). The most significant increase in D2 receptor density has been observed in studies that have used raclopride. The studies that have found decreased D1 receptor density have used the ligand SCH 23390, whereas increased D1 receptor density has been reported with 11C-NNC (4). Apparent contradictory findings, however, may be consistent with a single pathologic process—dopamine depletion. In rats chronic dopamine depletion is known to cause decreased binding of SCH 23390 (32,35) and increased binding of 11C-NNC (32).

A

B

C

Figure 21.2. Binding potential map of 11C-raclopride in a healthy volunteer showing ligand binding in the striatum (A, transaxial; B, sagittal; and C, axial view).

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In receptor imaging experiments, the activity of a neurotransmitter can be evaluated by either inducing or inhibiting its release, using a pharmacologic agent. The inducers reduce the BP of the ligand, and inhibitors have an opposite effect. It has been shown that the BP of raclopride is reduced after administration of amphetamine, which induces dopamine release (36). This reduction is exaggerated in schizophrenic patients (37–39), even if they are drug naive (40). The altered response to amphetamine in schizophrenia has been shown to be proportional to the severity of symptoms and therefore is observed only in the patients who have active symptoms (37). Depletion studies have also been conducted on schizophrenic patients, using a tyrosin analogue a-methyl-para-tyrosin (AMPT), which inhibits dopamine release. These studies have found that a higher proportion of D2 receptors are occupied by dopamine at basal level in schizophrenic patients as compared to healthy controls (41). All of these studies examined dopaminergic activity of postsynaptic neurons. Neurotransmitter imaging can also be used to evaluate presynaptic dopaminergic activity. Presynaptic dopamine activity can be evaluated by measuring DOPA decarboxylase activity, using the ligand 18 F-DOPA, or by studying dopamine transporter (DAT) activity. Imaging with 18F-DOPA has been used extensively to study Parkinson’s disease in which dopamine synthesis is reduced (42). It has also been used to study enhanced synthesis in schizophrenia (43). Presynaptic activity has however been studied mostly by imaging the DAT, which is involved in a number of neurologic and psychiatric disorders. Dopamine Transporter (DAT) The DAT is a plasma membrane protein, expressed exclusively by dopamine synthesizing neurons. By removing dopamine released into the extracellular space, it regulates the amplitude and duration of dopaminergic signals (44). Molecular imaging has played a major role in our understanding of the functions of DAT, and its involvement in disorders like Parkinson’s disease, attention-deficit hyperactivity disorder (ADHD), and drug abuse. The DAT has been imaged (Fig. 21.3) using a variety of cocaine (a DAT inhibitor) analogues [e.g., 11C-altropane, 123I-b-CIT, 18F-CFT and 123I-FP-CIT]. Because DAT density changes with the density of dopaminergic neurons, DAT ligands have been used to estimate neuronal loss in Parkinson’s disease. Reduction in BP of DAT ligands such as 123I-altropane (45) and 11 C-methylphenidate (46) has been documented in Parkinson’s disease (Fig. 21.4). Because Parkinsonian symptoms appear only after destruction of >85% of dopamine innervations, and because DAT tracers can detect a loss of as low as 50% of innervations, these tracers are useful for the diagnosis of early Parkinson’s disease in asymptomatic individuals (42,45,47). In addition to Parkinson’s disease, DAT imaging has been used extensively to study pathogenesis of ADHD (48,49). Though DAT binding is significantly elevated (20% to 70%) in adults (50) and children (51) with ADHD (Fig. 21.5), it is not clear whether its depletion is

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Figure 21.3. Binding potential map of 11C-altropane in a healthy volunteer.

NORMAL

MODERATE

SEVERE

Figure 21.4. 11C-altropane binding in a healthy volunteer (normal) and in patients with moderate and severe Parkinson’s disease.

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30

Cerebellum ADHD

25

Concentration

Striatum ADHD Cerebellum normal

20

Striatum normal 15

10

5

0 0

1000

2000

3000

4000

5000

Time (Sec.)

Figure 21.5. Concentration of 11C-altropane in the striatum, and in the reference region (cerebellum) in a healthy volunteer and in an attention-deficit/hyperactivity disorder (ADHD) patient. There is increased striatal binding in ADHD.

the cause of the disorder or is a reflective compensatory mechanism (49). It has been shown, however, that methylphenidate treatment downregulates the elevated DAT density in these patients (52,53). The DAT has also been associated with substance abuse (54). It has been shown that the degree of DAT blockade correlates positively with self-reported “high” following intravenous administration of cocaine or methylphenidate. Further, the abuse potential and dependency on these substances depends on the rate of DAT blockade. The incidence of dependency is greater if the blockade is faster. This is the reason why oral methylphenidate has lower abuse potential than cocaine administered parentally (55). Changes in DAT expression have been reported in a number of other disorders including dementia with Lewy bodies, Wilson’s disease, Tourette’s syndrome, and Lesch-Nyhan disease (44). The role of DAT in pathogenesis of these diseases, however, is uncertain because of a limited number of studies. Molecular imaging of the DAT has been used to elucidate the mechanism of actions of drugs that alter dopaminergic transmission. These studies have indicated that amphetamine promotes reverse transport of dopamine by internalizing DAT and making it available to intracellular dopamine, which is transported to the extracellular space. The internalization causes decrease in DAT activity (Bmax) on the cell surface. Cocaine, on the other hand, blocks the amphetamine-induced

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internalization and increases DAT expression, but it also attenuates DAT activity (56,57). Further, it has been shown that methamphetamine causes degeneration of dopamine nerve terminals, resulting in the loss of DAT binding in multiple brain regions (58–60).

Serotonergic System A number of radioligands have been developed to study serotonin [5-hydroxytryptamine (5HT2A and 5HT1A)] and serotonin transporter (SERT) activities. Commonly used ligands for serotonin receptors include 11C-WAY 100635, 18F-seroperone, and SERT ligands including 11 C-McN5652, 123I-ADAM, and 11C-DASB. Abnormal serotonin transmission has been implicated in a number of disorders, including major depression, epilepsy, and schizophrenia (61). Serotonergic receptors have been studied extensively to understand epileptic processes because they are believed to mediate antiepileptic and anticonvulsive effects through 5HT1A receptors located in the limbic area (62,63). Antiepileptic effect of serotonin is supported by studies that have found reduced binding of serotonin ligands (18F-MPPF and 18F-WAY) in epileptic zones of patients, as compared to the binding in the same areas of healthy controls. Further, the reduction is strongly correlated with the degree of epileptic activity (62,63). These results, however, are different from studies that have used a tryptophan (a serotonin precursor) derivative AMT, as ligand. These studies have found higher binding in the hippocampus of temporal lobe epilepsy (TLE) patients (64). Because AMT binding is positively correlated with the number of serotonergic neurons, it appears that receptor availability is reduced in epilepsy, even though there is an increase in serotonergic neurons. Another disorder that has been studied using serotonergic receptor imaging is major depression in which reduced uptake of the ligand 11CWAY 100635 is found in the cingulate, hippocampus, and midbrain of depressed patients (65). Studies that have used specific SERT ligands have not yielded definitive results because of their high nonspecific binding and slow clearance. These studies, however, have found lower binding of 11 C-McN5652, and 11C-DASB in multiple brain regions, most significantly in the striatal and limbic regions of depressed patients (61). Many investigators have studied the SERT using nonspecific transporter ligands. These studies have reported reduced binding of 123I-bCIT in mood disorders (66).

Other Neurotransmitter Systems g-Aminobutyric Acid g-Aminobutyric acid (GABA) is the most abundant inhibitory transmitter in the central nervous system and is distributed throughout the brain (2). A benzodiazepine derivative 11C-flumazenil (FMZ) has been

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used as a ligand to study GABA receptor activity in a variety of disorders that are associated with changes in GABAergic transmission. These disorders include schizophrenia, Huntington’s disease, Alzheimer’s disease, and epilepsy (67–75). Because GABA receptors are considered markers of neuronal loss (76), 11C-FMZ has been used to evaluate hippocampal atrophy in TLE by a number of investigators (77–79). These investigators have found that FMZ binding is a sensitive localizer of the regions of epileptic foci in intractable TLE. The localization of epileptic zones is more precise with FMZ than with FDG (80). Because resection of the areas of FMZ abnormalities is associated with excellent outcome, it is recommended that imaging studies using 11C-FMZ-PET be performed as a part of the routine surgical evaluation of TLE. In epileptic patients, the extent of FMZ-PET abnormalities correlates positively with the seizure frequency and duration of interictal period. Further, these abnormalities are corrected after surgery (81,82). Opiate Receptors The three types of opiate receptors (m, k, and d) are widely distributed in human brain. These receptors are involved in many pathologic conditions, including, addiction, Alzheimer’s disease, and epilepsy (83). A number of ligands are available for studying these receptors in humans (e.g., 11C-carfentanil, 11C-diprenorphine, 11C-buprenorphine, 18 F-cyclofoxy, 11C-naltrindole, and 11C-GR103545). Receptor imaging studies have shown that opiate receptors mediate addictive behavior by either stimulating (m receptors) or inhibiting (k receptors) the striatal dopamine system. Thus, high density of m receptors in the striatum is associated with alcohol dependence and craving (84). In Alzheimer’s disease, the binding of both m and k receptors is decreased (85). Binding studies in epileptic patients have yielded variable results. Although no change in opiate receptor density is found, if a nonspecific opiate receptor ligand 11C-diprenorphine is used, studies with the specific m-receptor ligand 11C-carfentanil are associated with increased binding at epileptic foci (86). It has also been shown that, after surgical removal of epileptic foci, the opiate receptors downregulate (87). Norepinephrine Alterations in the noradrenergic system have been reported in a number psychiatric disorders including depression and posttraumatic stress disorder. This system is also altered in Parkinson’s and Alzheimer’s disease (88). Most studies of norepinephrine neurotransmission have used ligands that bind to the norepinephrine transporter (NET), which is located on presynaptic noradrenergic neurons. Because of their location in presynaptic neurons, NET activity is considered an indicator of the density of norepinephrinergic neurons. A number of ligands have been developed to study the NET. These ligands include 11 C-talopram and 11C-talsupram. Because the NET represents an important target for a number of psychoactive compounds including some antidepressants and drugs of abuse, NET ligands may play an impor-

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tant role in the study of pathophysiology and pharmacotherapy of neuropsychiatric disorders. Alterations of the noradrenergic system have been reported in depressed patients and in postmortem brain tissue obtained from these patients (89). Further, decreased NET density is observed in the locus ceruleus of depressed individuals who committed suicide (90). Although the involvement of the noradrenergic system in mood disorders is well established, a unifying theory regarding the role of this system in depression has remained elusive. Imaging agents that evaluate NET activity can be a useful tool for clarifying the role of noradrenergic system in major depression. However, because the brain uptake of current NET ligands is very low, their application in neurotransmitter imaging is limited. Acetylcholine Cholinergic ligands are selective for either muscarinic or nicotinic receptors. Nicotinic receptors have been studied using 11C-nicotine and its derivatives. These studies have reported significant reduction (up to 50%) in the binding of these ligands in Alzheimer’s patients (67). The degree of reduction corresponds to the severity of cognitive impairment (68,69). Further, it has been shown that increase in receptor density (following treatment) correlates well with improvement in cognitive abilities of these patients (70). Because cholinergic receptor density parallels cognitive abilities, tracers that bind either to nicotinic or muscarinic receptors can be used to detect early Alzheimer’s disease. This condition can also be detected using tracers (e.g., 11C-MP4A-PET) that image acetylcholinesterase activity (71).

Dynamic Receptor Imaging The models used in conventional receptor imaging assume a steady state in which there is no change in synaptic concentration of endogenous neurotransmitter during the study. Therefore, these models cannot be used to detect acute changes in the amount of neurotransmitter released in response to a challenge, unless two separate scans (before and after the challenge) are performed. Separate scans, however, significantly reduce sensitivity and do not measure the gradient of change in neurotransmitter release. The conventional models, therefore, have been modified to allow detection of acute changes in neurotransmitter release. The modified models are particularly useful for the study of neurotransmission associated with a cognitive or behavioral task because these studies require comparison of the activated and control states and assume a change in the state during task performance. A number of simulation studies have been performed to evaluate the ability of these models to detect task-induced dynamic changes in synaptic concentration of neurotransmitters (91,92). These models prompted Koepp and colleagues to conduct an experiment and demonstrate that the BP of a dopamine ligand, raclopride, decreases significantly during performance of a goal-directed activity (11). The model

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used in this study, however, assumed a steady state. Consequently, the experiment was performed in two separate scan sessions. In one session, BP was measured while the volunteers were in the activated state (playing a video game). In the other, it was measured during a “no-activation” control condition. A comparison of BP measured in the two sessions indicated that dopamine is released during the task performance and that the release can induce measurable displacement of the ligand from receptor sites (93,94). However, because this method required two separate scan sessions, it is not considered sensitive enough to isolate changes induced by finer cognitive activities like memory and attention (5). Cognitive and behavioral studies are considered more sensitive if the two measurements are made in the same session. This issue was addressed to some extent by the development of a method for assessment of time-dependent changes in ligand displacement (95). This method allowed detection of ligand displacement in a single scan session. Using this approach, striatal dopamine release was detected during reward processing in healthy volunteers (12). In this experiment the rate of ligand displacement was increased relative to the rate observed in a control (no activation) task performed by a different group of volunteers. Moreover, the pattern of ligand displacement during activation was modeled using simulations. Because the control data were not specific to the subjects studied and the rate of ligand displacement was not derived from real data, the approach of this study was not ideal. This approach was modified by designing a method based on the simplified reference region model (96). In the modified method, an activation parameter was included in the model to quantify change in the rate of ligand displacement during task performance (5,9). By not assuming a steady state, this model allowed for fluctuations in synaptic concentration of endogenous transmitter. Using the data from a reference region (cerebellum) to estimate the effect of arterial input function (96), we explicitly modeled the kinetics of ligand delivery, receptor binding and dissociation, and the competition of ligand and endogenous neurotransmitter for the receptor. The solution of the differential equation of the model for the instantaneous concentration history of the tracer has the following form: t

t

PET (t) = R ◊ CR (t) + k 2 Ú CR (u)du - k 2 a Ú PET (u)du 0

0

t

- g Ú n(u - T )e - t ( u-T ) PET (u)du 0

where CR is the concentration of radioligand in a region devoid of specific binding (reference region), PET is the concentration of radioligand in a region with specific binding, R is the ratio of transport rates for the binding and reference regions, k2 describes the clearance of nonspecifically bound tracer, k2a includes the information about dissociation from the receptor, g represents the amplitude of transient effects, t denotes the measurement time, T is the task initiation time, and

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Concentration of 11C-Raclopride

396

0

30

60

Time(min)

Figure 21.6. Changes in the rate of displacement of 11C-raclopride in the left putamen during a motor planning task in healthy volunteers. The vertical lines indicate the time of task initiation, and the lowest line depicts displacement in a reference region (cerebellum). The figure also shows horizontal sections of the striatum from dorsal to ventral aspect in 2.4-mm steps (left striatum on the right). The t-map showing areas of significant changes (t > 3.0) in the rate of displacement is superimposed on the binding potential map (inset).

n(u - T) is the unit step function. Positive values of g represent taskrelated ligand displacement. Using this model we demonstrated the release of striatal dopamine during the performance of a variety of behavioral and cognitive tasks (Fig. 21.6). These tasks included motor planning, implicit motor memory, explicit motor memory and explicit cued recall (5–10). The dynamic receptor imaging method, at its current stage of development, has a number of limitations. It is not able to detect dopamine if the task induces release of a relatively small amount of neurotransmitter. Simulation experiments suggest that the method can detect dopamine release only if the change is >30% of baseline. The sensitivity of the method, however, can be enhanced by optimization of the signal-to-noise ratio (using advanced signal processing techniques). It can be further enhanced by averaging the data acquired from a cohort of subjects. Another limitation of the method is its inability to detect dopamine released in extrastriatal regions of the brain. Two newer ligands have kinetic properties that should favor detection of dopamine in the extrastriatal areas. These ligands are 18Ffallypride and 11C-FLB 457 (isoremoxipride). Experiments conducted on human volunteers and laboratory animals suggest that both of these

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ligands have high affinity for extrastriatal receptors and are displaced from the receptor sites by amphetamine-induced dopamine release (27,97,98). Even though dynamic receptor imaging has so far been used only for detection of striatal dopamine, it is theoretically possible to develop ligands that can detect release of other neurotransmitters in other brain areas. Such developments will go a long way in enhancing our understanding of human cognitive control.

Conclusion Neurotransmitter imaging has resulted in a considerable amount of new information concerning the pathogenesis of a number of neurologic and psychiatric conditions that include schizophrenia, addiction, Parkinson’s disease, Alzheimer’s disease, ADHD, epilepsy, anxiety, and affective disorders. Further, the use of these techniques in the diagnoses of subclinical Alzheimer’s and Parkinson’s disease in asymptomatic patients can help in early diagnosis and intervention. In addition, localization of epileptic foci by GABA receptor imaging has been shown to improve postsurgical clinical outcome. Neurotransmitter imaging for drug evaluation has aided in the development of new compounds that target specific receptors that are dysregulated in various disorders. Evolving molecular imaging techniques, like dynamic receptor imaging, offer even more exciting possibilities. These techniques can identify and localize areas of the brain where specific neurotransmitters are released during a task performance or symptom provocation. It will greatly expand our understanding of the fundamental alterations in neurochemistry in psychiatric and neurologic disorders. In addition, these methods will provide empirical data that can be used to formulate novel therapeutic strategies for treatment and prevention of the disorders that are associated with altered neurotransmission.

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A.J. Fischman and R.D. Badgaiyan 59. McCann UD, Wong DF, Yokoi F, Villemagne V, Dannals RF, Ricaurte GA. Reduced striatal dopamine transporter density in abstinent methamphetamine and methcathinone users: evidence from positron emission tomography studies with (11C)WIN-35,428. J Neurosci 1998;18:8417–8422. 60. Wilson JM, Kalasinsky KS, Levey AI, et al. Striatal dopamine nerve terminal markers in human, chronic methamphetamine users. Nat Med 1996;2: 699–703. 61. Parsey RV, Mann JJ. Applications of positron emission tomography in psychiatry. Semin Nucl Med 2003;33:129–135. 62. Merlet I, Ostrowsky K, Costes N, et al. 5–HT1A receptor binding and intracerebral activity in temporal lobe epilepsy: an (18F)MPPF-PET study. Brain 2004;127:900–913. 63. Toczek MT, Carson RE, Lang L, et al. PET imaging of 5–HT1A receptor binding in patients with temporal lobe epilepsy. Neurology 2003;60: 749–756. 64. Juhasz C, Chugani DC, Muzik O, et al. Alpha-methyl-L-tryptophan PET detects epileptogenic cortex in children with intractable epilepsy. Neurology 2003;60:960–968. 65. Farde L, Ginovart N, Ito H, et al. PET-characterization of (carbonyl11C)WAY-100635 binding to 5–HT1A receptors in the primate brain. Psychopharmacology (Berl) 1997;133:196–202. 66. Parsey RV, Mann JJ. Applications of positron emission tomography in psychiatry. Semin Nucl Med 2003;33:129–135. 67. Sihver W, Langstrom B, Nordberg A. Ligands for in vivo imaging of nicotinic receptor subtypes in Alzheimer brain. Acta Neurol Scand Suppl 2000;176:27–33. 68. Nordberg A, Hartvig P, Lilja A, et al. Decreased uptake and binding of 11Cnicotine in brain of Alzheimer patients as visualized by positron emission tomography. J Neural Transm Park Dis Dement Sect 1990;2:215–224. 69. Nordberg A, Lundqvist H, Hartvig P, Lilja A, Langstrom B. Kinetic analysis of regional (S)(-)11C-nicotine binding in normal and Alzheimer brains— in vivo assessment using positron emission tomography. Alzheimer Dis Assoc Disord 1995;9:21–27. 70. Nordberg A, Amberla K, Shigeta M, et al. Long-term tacrine treatment in three mild Alzheimer patients: effects on nicotinic receptors, cerebral blood flow, glucose metabolism, EEG, and cognitive abilities. Alzheimer Dis Assoc Disord 1998;12:228–237. 71. Yoshida T, Kuwabara Y, Ichiya Y, et al. Cerebral muscarinic acetylcholinergic receptor measurement in Alzheimer’s disease patients on 11C-Nmethyl-4—piperidyl benzilate—comparison with cerebral blood flow and cerebral glucose metabolism. Ann Nucl Med 1998;12:35–42. 72. Maziere M, Hantraye P, Prenant C, Sastre J, Comar D. Synthesis of ethyl 8–fluoro-5,6–dihydro-5–(11C)methyl-6–oxo-4H-imidazo (1,5–a) (1,4)benzodiazepine-3–carboxylate (RO 15.1788–11C): a specific radioligand for the in vivo study of central benzodiazepine receptors by positron emission tomography. Int J Appl Radiat Isot 1984;35:973–976. 73. Hammers A. Flumazenil positron emission tomography and other ligands for functional imaging. Neuroimaging Clin North Am 2004;14:537–551. 74. Matheja P, Ludemann P, Kuwert T, et al. Disturbed benzodiazepine receptor function at the onset of temporal lobe epilepsy—lomanzenil-binding in de-novo TLE. J Neurol 2001;248:585–591. 75. Mitterhauser M, Wadsak W, Wabnegger L, et al. Biological evaluation of 2¢-(18F)fluoroflumazenil ((18F)FFMZ), a potential GABA receptor ligand for PET. Nucl Med Biol 2004;31:291–295.

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Chapter 21 Neurotransmitter Imaging 76. Heiss WD, Graf R, Fujita T, Ohta K, Bauer B, Lottgen J, Wienhard K. Early detection of irreversibly damaged ischemic tissue by flumazenil positron emission tomography in cats. Stroke 1997;28:2045–2051; discussion 2051– 2052. 77. Savic I, Pauli S, Thorell JO, Blomqvist G. In vivo demonstration of altered benzodiazepine receptor density in patients with generalised epilepsy. J Neurol Neurosurg Psychiatry 1994;57:797–804. 78. Koepp MJ, Richardson MP, Brooks DJ, et al. Cerebral benzodiazepine receptors in hippocampal sclerosis. An objective in vivo analysis. Brain 1996;119:1677–1687. 79. Debets RM, Sadzot B, van Isselt JW, et al. Is 11C-flumazenil PET superior to 18FDG PET and 123I-iomazenil SPECT in presurgical evaluation of temporal lobe epilepsy? J Neurol Neurosurg Psychiatry 1997;62:141–150. 80. Juhasz C, Chugani DC, Muzik O, et al. Relationship of flumazenil and glucose PET abnormalities to neocortical epilepsy surgery outcome. Neurology 2001;56:1650–1658. 81. Bouvard S, Costes N, Bonnefoi F, et al. Seizure-related short-term plasticity of benzodiazepine receptors in partial epilepsy: a (11C)flumazenil-PET study. Brain 2005;128:1330–1343. 82. Savic I, Svanborg E, Thorell JO. Cortical benzodiazepine receptor changes are related to frequency of partial seizures: a positron emission tomography study. Epilepsia 1996;37:236–244. 83. Machulla HJ, Heinz A. Radioligands for brain imaging of the kappa-opioid system. J Nucl Med 2005;46:386–387. 84. Bencherif B, Wand GS, McCaul ME, et al. Mu-opioid receptor binding measured by (11C)carfentanil positron emission tomography is related to craving and mood in alcohol dependence. Biol Psychiatry 2004;55:255– 262. 85. Cohen RM, Andreason PJ, Doudet DJ, Carson RE, Sunderland T. Opiate receptor avidity and cerebral blood flow in Alzheimer’s disease. J Neurol Sci 1997;148:171–180. 86. Prevett MC, Cunningham VJ, Brooks DJ, Fish DR, Duncan JS. Opiate receptors in idiopathic generalised epilepsy measured with (11C)diprenorphine and positron emission tomography. Epilepsy Res 1994;19:71–77. 87. Bartenstein PA, Prevett MC, Duncan JS, Hajek M, Wieser HG. Quantification of opiate receptors in two patients with mesiobasal temporal lobe epilepsy, before and after selective amygdalohippocampectomy, using positron emission tomography. Epilepsy Res 1994;18:119–125. 88. McConathy J, Owens MJ, Kilts CD, et al. Synthesis and biological evaluation of (11C)talopram and (11C)talsupram: candidate PET ligands for the norepinephrine transporter. Nucl Med Biol 2004;31:705–718. 89. Ressler KJ, Nemeroff CB. Role of norepinephrine in the pathophysiology of neuropsychiatric disorders. CNS Spectr 2001;6:663–666, 670. 90. Klimek V, Stockmeier C, Overholser J, et al. Reduced levels of norepinephrine transporters in the locus coeruleus in major depression. J Neurosci 1997;17:8451–8458. 91. Morris ED, Fisher RE, Alpert NM, Rauch SL, Fischman AJ. In vivo imaging of neuromodulation using positron emission tomography: optimal ligand characteristics and task length for detection of activation. Hum Brain Map 1995;3:35–55. 92. Fisher RE, Morris ED, Alpert NM, Fischman AJ. In vivo imaging of neuromodulatory synaptic transmission using PET: A review of relevant neurophysiology. Hum Brain Map 1995;3:24–34.

A.J. Fischman and R.D. Badgaiyan 93. Dewey SL, MacGregor RR, Brodie JD, et al. Mapping muscarinic receptors in human and baboon brain using (N-11C- methyl)-benztropine. Synapse 1990;5:213–223. 94. Seeman P, Guan HC, Niznik HB. Endogenous dopamine lowers the dopamine D2 receptor density as measured by (3H)raclopride: implications for positron emission tomography of the human brain. Synapse 1989;3:96–97. 95. Friston KJ, Malizia AL, Wilson S, Cunningham VJ, Jones T, Nutt DJ. Analysis of dynamic radioligand displacement or “activation” studies. J Cereb Blood Flow Metab 1997;17:80–93. 96. Gunn RN, Lammertsma AA, Hume SP, Cunningham VJ. Parametric imaging of ligand-receptor binding in PET using a simplified reference region model. Neuroimage 1997;6:279–287. 97. Mukherjee J, Yang ZY, Lew R, et al. Evaluation of d-amphetamine effects on the binding of dopamine D-2 receptor radioligand, 18F-fallypride in nonhuman primates using positron emission tomography. Synapse 1997; 27:1–13. 98. Chou YH, Halldin C, Farde L. Effect of amphetamine on extrastriatal D2 dopamine receptor binding in the primate brain: a PET study. Synapse 2000;38:138–143.

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22 Cardiovascular Applications Miguel Hernandez-Pampaloni

An improved understanding of the pathophysiology of myocardial ischemia combined with the development of new diagnostic modalities has substantially modified the concepts of myocardial blood flow (MBF) and left ventricular function in coronary artery disease (CAD). Positron emission tomography (PET) has emerged as a unique tool to characterize physiologic and pathologic processes, and it already plays a significant role in different areas of clinical medicine, including cardiology. Cardiac PET is based on the properties of positron emitters and radiation detection to provide a noninvasive and in vivo assessment of regional myocardial perfusion and metabolism. Different study protocols have been largely used in the adult population to detect and grade the severity of coronary artery disease during the last two decades using cardiac PET technology. Further, cardiac PET using fluorine-18 (18F) 2-fluoro-2-deoxyglucose (FDG) is considered the gold standard imaging modality for the assessment of myocardial viability (1) and is well recognized as providing accurate information on the long-term prognosis of the patients with chronic coronary ischemic disease (2). Positron emission tomography offers unique capabilities for noninvasive assessment of regional myocardial function and can disclose information of utmost importance for the more accurate understanding of pathophysiologic processes and for the optimal management of the diseased patient. By detecting the very early functional regional abnormalities before the development of more severe structural changes, PET imaging can be useful in providing improved and preventive care to the patient. Thus, cardiac PET imaging can offer a more comprehensive understanding of the normal myocardial physiology and early recognition of functional abnormalities. This is even more important in pediatric cardiology where the early detection of myocardial dysfunction may be helpful in choosing the appropriate management for the prevention of long-term consequences. Recent surgical and technical advances in pediatric cardiology make even more important an accurate detection of potentially treatable coronary abnormalities. Positron emission tomography imaging’s high spatial and 407

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temporal resolution provides better image quality, especially important in small pediatric hearts, and it allows the quantification in absolute terms of the MBF and regional myocardial metabolism. Single photon emission computed tomography (SPECT) imaging quality is usually limited by poor resolution and the low usable activity of thallium 201 (201Tl), whereas images obtained after the administration of technetiumlabeled compounds are compromised by the high liver activity in close proximity to the small heart. This chapter describes the basic principles of PET applied to the study of the heart, and presents the current and potential future clinical applications of cardiac PET in pediatric patients.

Principles of Emission Tomography Applied to the Cardiovascular System Positron emission tomography imaging features are based on the physical properties of the positron decay. A positron has the same characteristics as an electron, except for its positive charge. Positrons are emitted from unstable nuclei (that have an excess of protons) that dispose of their excess charge by emitting a positron. At the end of the positron range, after losing its kinetic energy, a positron combines with an electron and the two particles annihilate. The annihilation coincidence detection of the two colinear 511-keV gamma rays photons, emitted in diametrically opposite directions by opposing scintillator detectors, is the essence of the PET imaging formation (3). To detect the location of the annihilation event, detectors are placed on opposite sides of the source and are connected in a coincidence detection circuit. When a given event is recorded simultaneously, positron annihilation is assumed to have taken place on the line between the detectors, and hence the location can be accurately determined. Radiopharmaceuticals Cardiac PET studies are performed with radiopharmaceuticals specifically synthesized to assess determined cardiac functions or biochemical processes and with radiopharmaceuticals that have applications in other disciplines. The radiolabeled positron-emitting tracers used in cardiac PET studies are produced by a cyclotron or by a generator system. Currently, different processes of the heart have been studied using different radiopharmaceuticals (Table 22.1). The radiation exposure to PET radiotracers is lower compared to other radionuclides used for nuclear cardiology studies (Table 22.2). Evaluation of Myocardial Blood Flow The development of suitable radiotracers and appropriate mathematical models applied to PET imaging has been shown to allow for the noninvasive and accurate quantification of regional MBF. Different radiotracers have been used for measuring MBF, including nitrogen13–labeled ammonia (13NH3) (4–6), oxygen-15 (15O)-labeled water (15O-

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Table 22.1. Principal PET tracers for cardiac imaging Radionuclide 13 N 82 Rb 15 O

Radiopharmaceutical Ammonia Rubidium chloride Water

18

Deoxyglucose Acetate palmitate

F C

11

Physical half-life 10.0 min 78 s 2.0 min

Mean positron range 0.7 mm 2.6 mm 1.1 mm

Production Cyclotron Generator Cyclotron

110 min 20 min

0.2 mm 0.28 mm

Cyclotron Cyclotron

H2O) (7–9), the potassium analogue rubidium-82 (82Rb) (10), copper-62 (62Cu)-pyruvaldehyde bis(N4-methylthio-semicarbazone (62Cu-PTSM) (11,12), gallium-68 (68Ga)-labeled albumin microspheres (13), and potassium 38 (38K) (14). The choice of a specific radiotracer is finally frequently determined by different factors besides their physical properties, such as an individual institution’s preference, experience, or accessibility. Currently, 13NH3, 15O-H2O, and 82Rb are the most widely used PET perfusion tracers. Generator-produced 82Rb has the advantages of not requiring a cyclotron and having a very short half-life (78 seconds), making it attractive for one-session rest/stress imaging. 82Rb has a low first-pass myocardial extraction fraction (50% to 60%) that results in a nonlinear uptake in relation to blood flow, particularly at high flow rates (15). As a potassium analogue, 82Rb is retained in the myocardium and equilibrates with the cellular potassium pool. Because of the dependence on the flow rate and the metabolic state,

Table 22.2. Dosimetry in cardiac pediatric nuclear medicine 99m

Newborn (3.5 kg) 1-yr-old (10 kg) 5-yr-old (18 kg) 10-yr-old (31 kg) 15-yr-old (56 kg) Adult (70 kg) Critical organ

201 13 Tc-sestamibi Tl N-ammonia Effective dose equivalent (mSv/MBq) 0.120 11.00 0.0320 0.058 6.90 0.0130 0.041 4.90 0.0067 0.027 4.10 0.0043 0.019 0.68 0.0028 0.015 0.34 0.0022 Kidney Kidney Bladder wall

Newborn (3.5 kg) 1-yr-old (10 kg) 5-yr-old (18 kg) 10-yr-old (31 kg) 15-yr-old (56 kg) Adult (70 kg)

Dose equivalent per body weight 0.89 12.22 0.34 0.43 7.67 0.14 0.30 5.44 0.07 0.20 4.56 0.05 0.14 0.76 0.03 0.11 0.38 0.02

18

F-FDG

0.310 0.100 0.077 0.050 0.038 0.030 Bladder wall 1.64 0.69 0.41 0.26 0.20 0.16

Source: Modified from Radiopharmaceutical Internal Dose Information Center, Oak Ridge Associated Universities, Oak Ridge, Tennessee.

Cardiac application Blood flow Blood flow Blood flow, perfusable tissue index Glucose metabolism Blood flow, oxygen consumption fatty acid metabolism

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situations of hyperemia or metabolically impaired myocardium may limit the accuracy for quantifying MBF. 13NH3 is a cyclotron-generated myocardial perfusion tracer with a high first-pass extraction fraction, a high tissue-to-blood contrast ratio within minutes following the radiotracer administration, and a relatively short half-life (9.8 minutes) that makes it also suitable for one-session studies. 13NH3 is metabolically trapped in the myocardium based on the glutamine synthetase action. Under physiologic resting blood flow, the rate of metabolic conversion of 13NH3 to glutamine inside the myocytes is sufficiently elevated to convert and retain a major fraction of 13NH3 delivered to the myocardial tissue. However, in conditions of high flow, the amount of 13NH3 delivered to the myocardial tissue exceeds the rate of conversion to glutamine, and therefore a significant amount of 13NH3 is returned to the capillary blood and removed from the tissue. To overcome this nonlinear response to conditions of high flow rate, different kinetic modeling approaches have been developed (16,17). To minimize the limited spatial resolution of PET systems and the intrinsic motion of the heart, additional corrections have been included to account for the impact of the partial volume effect and spillover fraction (18,19). 15 O-H2O has several attractive properties as a myocardial perfusion tracer including a high first-pass extraction fraction (nearly 100%), a freely diffusible uptake and washout mechanism limited only by myocardial perfusion, a much reduced accumulation of the tracer in background organs, and finally a short half-life (122 seconds) that permits repeated and sequential blood flow measurements. However, the rapid washout of 15O-H2O requires corrections to achieve a good tissue–blood contrast, necessary for an accurate MBF quantification. To correct for the high activity of 15O-H2O in the blood pool, an additional 15 O–carbon monoxide blood pool scanning, which binds hemoglobin in the red blood cells, was required to define regions of interest and delineate the vascular space. These correction techniques have recently been optimized by the generation of myocardial images directly from dynamic 15O-H2O scans, not requiring the 15O-carbon monoxide blood pool scan (20,21). Evaluation of Fatty Acid Metabolism and Oxygen Consumption Cardiomyocytes metabolize various substrates as source of energy. Under fasting conditions, free fatty acids are the primary source of energy. Free fatty acids are extracted by the myocardium and, after the formation of long-chain acyl–coenzyme A (CoA), predominantly enter the mitochondria to suffer b-oxidation prior to going into the tricarboxylic acid cycle. The rate of fatty acid oxidation is controlled by the rate of transfer into the mitochondria. 11C-palmitate, a 16-carbon, longchain fatty acid, was the first PET radiotracer used to assess regional cardiac metabolism. Clearance of 11C-palmitate follows a bioexponential kinetic model. The initial rapid-phase clearance reflects the immediate oxidation and the elimination of carbon dioxide. The second phase is believed to represent the incorporation of the radiotracer into

M. Hernandez-Pampaloni Glucose (18F-FDG) Lactate

Hexobinase Lactate Glucose-6-phosphate

Pyruvate

Glycogen

Mitochondria PDH Triglycerides Phospholipids

Acyl-Camitine

Camitine TCA Acyl-CoA

α-GP

CPTI

β-oxidation Acety1-CoA

Acyl-CoA

CO2

Myocyte Free Fatty Acids (11C-Palmitate)

CO2

11C-Acetate

CO2

Figure 22.1. Radiotracers that can be used by PET to investigate different myocardial metabolic pathways.

the lipid metabolism as triglycerides and its final oxidation (22). The kinetics of 11C-palmitate may theoretically be useful to evaluate cardiac metabolism in situations of ischemic compromise. During ischemia, the rate of elimination of 11C-palmitate is decreased with a reduced oxidation of fatty acids. On the other hand, the increased cardiac work would produce an accelerated clearance of the radiotracer as the oxidative metabolism would be increased. However, the main disadvantage of this compound is the complexity of its kinetics because a very rapid clearance from the blood pool and b-oxidation allows only a very short time of analysis (Fig. 22.1). To overcome the limitations presented by 11C-palmitate, 11C-acetate has been proposed as an alternative to evaluate oxidative cardiac metabolism (23,24). 11C-palmitate is extracted proportionally to MBF with a first-pass extraction fraction of approximately 50% under resting conditions. Once inside the myocyte, 11C-palmitate is converted to 11Cacetyl-CoA, which enters the tricarboxylic acid cycle in the mitochondria (21,22). Clearance of 11C activity in the form of 11C-CO2 does not occur for 4 to 5 minutes after tracer delivery, reflecting MBF except in conditions of high oxygen demand. Kinetics of 11C-palmitate has allowed the quantification of oxygen consumption from the myocardial clearance rate as a parameter of the oxidative metabolism and MBF

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and its correlation with the presence of ischemia when this oxygen consumption diminishes (25–27). Evaluation of Glucose Metabolism In contrast to fasting conditions where free fatty acids predominate as a source of myocardial energy, after an ingestion of carbohydrates plasma glucose and insulin levels increase and levels of free fatty acids decline. In response, oxidation of free fatty acids decreases and utilization and oxidation of glucose increases. When myocardial ischemia ensues, contractile function declines, oxidation of free fatty acids decreases, and uptake and metabolism of glucose increase. Then glucose transport and metabolism are upregulated during ischemic conditions and after the complete resolution of these episodes, most likely due to an upregulation of the glucose transporter GLUT-1 (28,29). Regional cardiac glucose metabolic activity can be assessed with 18FFDG. The positron emitter 18F (with a half-life of 109 minutes) linked to the glucose analogue FDG, passes the cellular membrane through facilitated diffusion, mostly mediated by the insulin-sensitive protein carrier GLUT-4 (30). Inside the myocyte the radiotracer is subjected to the first step of glycolysis by a hexokinase-mediated phosphorylation to FDG-6-phosphate. The phosphorylated glucose analogue becomes metabolically trapped in the myocardium so that the regional tracer activity concentrations reflect regional rates of exogenous glucose utilization. A more favorable standardized assessment of myocardial glucose utilization has been achieved assuming the conditions would have remained the same under physiologic and pathophysiologic conditions, by applying the so-called lumped constant, which corrects for the different kinetics affinities between 18F-FDG and glucose itself (31). Noninvasive approaches that assess exogenous glucose utilization, therefore, play an important role in the evaluation of myocardial viability in patients with coronary ischemic disease and left ventricular dysfunction. Because dysfunctional myocardium that can recover function after revascularization must retain sufficient blood flow and metabolic activity to sustain myocytes, the combined assessment of regional MBF and glucose metabolism provides additional and invaluable information. Interpretation of PET Data The acquisition of cardiac PET data can be achieved in either the static or dynamic mode. For static acquisitions prior to imaging, time is allowed after the injection of the radiotracer for adequate clearance from the bloodstream and uptake from the myocardium to obtain adequate myocardial-to-background activity ratios. Static imaging depicts the relative distribution of the radiotracers in the myocardium and is used for a semiquantitative or qualitative analysis of the distribution of the radiotracers within different regions of the myocardium. This approach, however, does not allow accurate quantifying functional myocardial processes. Imaging cardiac PET data are routinely

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acquired in transaxial slices with a field of view of approximately 10 to 15 cm. Reconstruction of the attenuation-corrected projection data is usually performed by filtered backprojection. Specific software is used to realign the image information perpendicular to the long axis of the left ventricle. This allows the visualization of the radiotracer distribution along the short and long axes of the left ventricle. The interpretation of the images is based on the visualization of the short, vertical, and horizontal long axes based on the relative regional distribution of the tracer (32). Further, the evaluation of circumferential profile analysis provides a more objective way to measure regional tracer differences and is based on specific analysis software packages, similar to that introduced for SPECT analysis (5,6). For the objective assessment of myocardial perfusion defects, individual patient data are compared with a database of normal controls. The assessment of regional myocardial defects is expressed as a percentage of pixels below two standard deviations of the control population for the corresponding area of myocardium. Detailed knowledge of the myocardial biochemical processes is required to accurately analyze different patterns of the uptake of myocardial blood flow (13N-ammonia, 15O-H2O, 82Rb) and myocardial metabolism radiotracers (18F-FDG). Three patterns of blood flow–metabolism uptake have been described in adults and largely used to analyze severe dysfunctional myocardium for assessing the presence of recoverable and, hence, viable myocardium (4). A normal distribution of the flow radiotracer regardless of the uptake of 18F-FDG is seen in normal myocardium. On the other hand, absent or severely reduced regional blood flow and glucose metabolism is observed in akinetic and dyskinetic myocardium and represents myocardial necrosis. This pattern is described as a “match defect.” Finally, the maintained reduced blood flow to the myocardium produces an adaptation with a normal or slightly reduced uptake of 18F-FDG. This reduced or absent MBF with normal or slightly reduced glucose metabolism within the myocytes indicates myocardial hibernation and therefore viability. This pattern, described as a “mismatch pattern,” characterizes severe dysfunctional myocardium supplied by a stenotic or almost totally occluded coronary artery (Fig. 22.2). The restoration of blood flow to these myocardial regions results in recovery of contractile function and normalization of the glucose metabolism (33,34). This more probably occurs after a period of time, described as stunned myocardium, where glucose metabolism may remain elevated with a normalized blood flow and a not entirely recovered contractile function. Positron emission tomography cardiac radiotracers and physical properties of the PET system enable the absolute quantification of myocardial biochemical processes, such as myocardial blood flow and glucose metabolism. This is based on the short half-life and high energy of the radiotracers and the high temporal and spatial resolution of the current PET systems that provides the ground to accurately measure rapid changes in tissue tracer concentrations. Quantification of myocardial processes requires dynamic acquisition and the application of

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FDG

Horizontal Vertical Long Axis

Short Axis

Figure 22.2. Reoriented images of the myocardial 13N-ammonia (upper panel) and 18F-FDG uptake (lower panel) in a patient with transposition of the great arteries after the arterial switch operation. Note the impaired perfusion in the anterolateral wall (arrows), evidenced by the decreased uptake of 13Nammonia, whereas the myocyte metabolism of 18F-FDG is preserved, indicating viable myocardium. (Courtesy of Dr. Heinrich Schelbert, David Geffen School of Medicine, Los Angeles.)

tracer kinetic models (5,35). This means that the images are acquired by the system from the time of the tracer injection through a point of steady-state flux. Sampling with high temporal resolution is required to define the changes in radioactivity in the blood and the myocardial region of interest. The rapid sequential sampling and imaging enables the determination of the tracer delivery via the arterial plasma to the region of interest to define the arterial input function and the consequent tissue response to this input function. Arterial input function is generally defined by regions of interest placed over the left atrium or left ventricle to obtain temporal changes in radioactivity concentration in the different heart chambers. The rapid dynamic acquisition along with a late time frame enables the derivation of a myocardial tissue time-activity curve (19). Dynamic acquisition, with its high volume of data, requires specific interactive software for image reconstruction, quantitative analysis, and visual presentation. The obtained regional MBF is expressed in milliliters per minute per 100 g of tissue, glucose utilization in micromoles per minute per gram of tissue, oxygen consumption in micromoles per minute per 100 g of tissue, and coronary flow reserve as the ratio of stress and resting myocardial perfusion.

M. Hernandez-Pampaloni

Cardiac PET Protocols Positron emission tomography studies in the pediatric population require special considerations for patient preparation and the data acquisition process. Experience in performing pediatric studies and expertise in dealing with pediatric patients will optimize the outcome of the entire study procedure minimizing the discomfort to the patients. A cardiac PET study requires the patient to remain still for the entire duration of the study. A routine myocardial blood flow– metabolism study may last up to 2 hours, and a rest/stress myocardial perfusion study may last up to 90 minutes. Thus, unlike adults, most pediatric patients would require sedation before the study is performed. This is especially necessary for infants and young children. Several intravenous premedication protocols have been used, mostly including chloral hydrate or midazolam (36,37). Due to the length of the study, further intravenous sedation may be necessary. Baseline vital signs (electrocardiogram, blood pressure, and heart rate) along with transcutaneous pulse oximetry should be recorded and monitored throughout the study. Myocardial perfusion imaging and coronary reserve studies consist of a resting and stress examination using either pharmacologic stress (dipyridamole or adenosine) or exercise (ergometric bicycle). Patients should refrain from eating or drinking anything except water for 4 hours before the procedure, and they should abstain from caffeinecontaining drinks or medications containing theophylline for 8 hours before. Adolescents should avoid cigarettes for at least 8 hours as well. Studies involving metabolic imaging with 18F-FDG require a standardization of the substrate availability that optimizes myocardial glucose uptake. Older children and adolescents are routinely fasted overnight, and an oral glucose load dose is given 1 hour prior to the 18F-FDG injection to facilitate glucose uptake in the myocardium. It is important to ascertain any history of diabetes or intolerance to glucose to ensure that proper steps are taken to optimize myocardial glucose uptake. Blood glucose monitoring during the study should be performed routinely to ensure that metabolic conditions are maintained along the entire acquisition process.

Clinical Applications Coronary abnormalities, with impairments of regional myocardial perfusion, are a relevant cause of morbidity and mortality in the pediatric population. Although the experience of cardiovascular PET in pediatrics remains somewhat limited, this technique has been applied in several congenital and acquired heart diseases, providing new insights into the diseased pediatric heart and optimizing the clinical management of these patients. Recent surgical and technical advances have provided better treatment and long-term prognosis for many complex pediatric heart diseases, making the accurate diagnosis of ischemic but potentially recoverable myocardium even more important.

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Transposition of the Great Arteries In infants with transposition of the great arteries (TGA), correct cardiac anatomy is surgically restored by the arterial switch operation (ASO) of aorta and pulmonary artery. As the coronary arteries need to be excised and reinserted in the neo-aorta during the procedure, the longterm success of this operation is based on the continued patency and adequate functioning of the coronary arteries. The findings that postsurgical coronary occlusions have been described angiographically (38) and that acute myocardial infarctions and sudden deaths have been reported (39) in up to 10% of this patient population emphasize the prognostic implications of this issue. Regional reversible perfusion abnormalities were initially described by using exercise technetium99m-sestamibi SPECT in patients following ASO (40). In contrast to SPECT imaging, higher spatial resolution of PET systems have allowed for the absolute quantification of MBF. Bengel et al. (41) were the first to report regional perfusion abnormalities with adenosine 13Nammonia PET in patients with no ischemic symptoms late after the ASO, with no correlation with any echocardiographic contractile dysfunction. They found a lower incidence of reversible perfusion defects when compared to the previous SPECT imaging studies, but quantitative hyperemic MBF and coronary flow reserve in response to adenosine were significantly lower in the patients after ASO, when compared to young healthy individuals. Similar results were described by others, which suggests that the global impairment of maximal MBF may represent alterations in the myocardial normal vasoreactivity as the early manifestation of changes in the coronary microcirculation (42). However, the procedure of coronary reimplantation alone seems to be not the only factor responsible for the myocardial perfusion abnormalities. By comparing two groups of patients with transposition of the great arteries, one after the ASO and the second after the Ross procedure to treat aortic valve disease with 13N-ammonia adenosine PET, Hauser et al. (43) reported that in contrast to the patients who underwent the Ross operation, stress-induced perfusion defects and a diminished coronary flow reserve were documented in the patients after the ASO. Further follow-up and more extensive investigations are necessary to fully understand the etiology of these findings and to determine whether the reported myocardial perfusion abnormalities have significant long-term prognostic implications in these patients. Metabolic 18F-FDG imaging, along with myocardial perfusion assessment can provide useful information to identify viable but dysfunctional myocardium in patients who develop an acute cardiac event after the ASO or as a result of other coronary abnormalities. Rickers et al. (44) stated that 18F-FDG–gated PET demonstrated viable myocardium in akinetic or hypokinetic regions subtended by stenotic coronary arteries after the ASO. Based on their findings, they treated patients surgically with coronary revascularization if viable myocardium was identified, whereas the patients with impaired glucose uptake, indicating myocardial scarring, were treated medically. To establish the accuracy of metabolic and perfusion PET imaging in

Figure 13.3. Positron emission tomography–computed tomography (PET-CT) coronal images of a 4-year-old girl with refractory neuroblastoma following bone marrow transplantation. A: CT scan. B: FDG-PET scan with attenuation correction. C: Fusion image of CT scan and FDG-PET scan with attenuation correction. D: FDG-PET scan without attenuation correction. Abnormal uptake of FDG in the abdomen is seen to the right of the midline medial to the liver, representing residual neuroblastoma.

E

F Figure 20.6. E: Statistical pixel analysis map in transverse section of significant ictal rCBF greater than interictal rCBF (yellow) or less that interictal rCBF (blue). Map shows significant ictal associated hyperemia in the region of the angioma. F: Statistical pixel analysis map in sagittal section of significant ictal rCBF greater than interictal rCBF (yellow) or less that interictal rCBF (blue). Map shows significant ictal associate hyperemia anterior to the angioma.

NH3 – Perfusion

FDG – Fasting

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Figure 22.3. Reoriented images of the myocardial 13N-ammonia (upper panel) and fasting 18F-FDG uptake (lower panel) in a patient with transposition of the great arteries who had an acute episode of chest pain late after the arterial switch operation. Note the impaired perfusion in the anterolateral wall evidenced by the decreased uptake of 13N-ammonia, whereas the myocyte metabolism of 18F-FDG is preserved, indicating viable myocardium in that myocardial regions. (Courtesy of Dr. Heinrich Schelbert, David Geffen School of Medicine, Los Angeles.)

NH3 – Rest

NH3 – Stress (dipyridamole)

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Figure 22.4. Reoriented images of the myocardial resting 13N-ammonia (upper panel) and after dipyridamole-induced stress 13N-ammonia (lower panel) PET study in a patient with anomalous origin of the left coronary artery arising from the pulmonary artery (ALCAPA). Note the fixed defect in the anterolateral wall that corresponds to an acute myocardial infarction in that region. (Courtesy of Dr. Heinrich Schelbert, David Geffen School of Medicine, Los Angeles.)

Figure 27.2. Three-dimensional (3D) reconstruction of a registered image data set. The cortical surface was rendered from MRI and red dots represent subdural EEG electrodes that were imaged with CT. The functional epileptogenic focus (orange) was defined by interictal fluorodeoxyglucose (FDG)-PET and ictal ECD– single photon emission computed tomography (SPECT).

A

B Figure 27.3. Histologically proven nonaffected cystic ovary in a patient with a recurrent yolk sack tumor: T1weighted, fat-suppressed MR sequence after application of gadolinium– diethylenetriamine pentaacetic acid (Gd-DTPA) (A) depicts a physiologicappearing cystic ovary (arrow). Corresponding PET (B) revealed a false-positive finding with an increased glucose uptake (arrow) suspect of a recurrent disease. Multimodality display of registered images (C) shows exact spatial correlation between the cystic ovary in MRI and increased glucose uptake in PET.

C

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FDG – Fasting

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Figure 22.3. Reoriented images of the myocardial 13N-ammonia (upper panel) and fasting 18F-FDG uptake (lower panel) in a patient with transposition of the great arteries who had an acute episode of chest pain late after the arterial switch operation. Note the impaired perfusion in the anterolateral wall evidenced by the decreased uptake of 13N-ammonia, whereas the myocyte metabolism of 18F-FDG is preserved, indicating viable myocardium in that myocardial regions. (Courtesy of Dr. Heinrich Schelbert, David Geffen School of Medicine, Los Angeles.) (See color insert.)

detecting myocardial viability in children with myocardial dysfunction and its correlation with histopathological changes, HernandezPampaloni et al. (45) studied a group of patients with different suspected coronary abnormalities after an acute cardiac event (Fig. 22.3, see color insert). They reported good agreement between the findings on myocardial perfusion PET and metabolic imaging with those on coronary angiography, echocardiography, and histopathology. Anomalous Origin of the Left Coronary Artery Arising from the Pulmonary Artery Anomalous origin of the left coronary artery arising from the pulmonary artery (ALCAPA) is a rare but serious congenital anomaly. It does not present prenatally because of the favorable fetal physiology that includes (1) equivalent pressure in the main pulmonary artery and aorta secondary to a nonrestrictive patent ductus arteriosus, and (2) relatively equivalent oxygen concentrations due to parallel circulations. As a result, myocardial perfusion is normal, and there is no stimulus for collateral formation between the right and left coronary artery

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NH3 – Rest

NH3 – Stress (dipyridamole)

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Short Axis UCLA PET W.F. p04356

Figure 22.4. Reoriented images of the myocardial resting 13N-ammonia (upper panel) and after dipyridamole-induced stress 13N-ammonia (lower panel) PET study in a patient with anomalous origin of the left coronary artery arising from the pulmonary artery (ALCAPA). Note the fixed defect in the anterolateral wall that corresponds to an acute myocardial infarction in that region. (Courtesy of Dr. Heinrich Schelbert, David Geffen School of Medicine, Los Angeles.) (See color insert.)

systems. In the few weeks after birth, pulmonary artery pressure and resistance progressively decrease with a simultaneous decrease in oxygen content of pulmonary blood flow as the circulation becomes one in series. This results in the left ventricular myocardium being perfused by relatively desaturated blood under low pressure, leading to myocardial ischemia. Initially, myocardial ischemia is transient, occurring during periods of increased myocardial demands, such as when the infant is feeding and crying. Further increases in myocardial oxygen consumption lead to infarction of the anterolateral left ventricular free wall (Fig. 22.4, see color insert). This may lead to possible mitral valve papillary muscle dysfunction and variable degrees of insufficiency. Following surgical repair to establish blood flow to the left coronary arteries from the aorta, left ventricle (LV) function recovers and usually normalizes within 2 to 3 years. Perfusion abnormalities, however, are not uncommon in long-term survivors. Long-term survivors of ALCAPA repair demonstrate regional impairment of myocardial flow reserve. This may contribute to impaired exercise performance by limiting cardiac output reserve (46). Patients with severely reduced regional coronary flow reserve may be at risk of exercise-

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induced ischemic events. Thus, accurate identification of these patients by PET imaging can be of help regarding physical activity, antiischemic measures, and revascularization. Kawasaki Disease Kawasaki disease, also known as mucocutaneous lymph node syndrome, is an acute vasculitis that mostly affects infants and children under 5 years of age. It causes an acute vasculitis, particularly affecting medium-sized arteries such as the coronary arteries (47). The etiology and pathogenesis of Kawasaki disease remains unknown, although clinical and epidemiologic data support an infectious cause. The clinical features of Kawasaki disease can be divided into three phases. The first, or acute, phase lasts about 10 days and is marked by a temperature as high as 40°C accompanied by a polymorphous exanthem. Cardiac manifestations during this phase may include tachycardia, gallop rhythm, congestive heart failure, pericardial effusion, and arrhythmias. Arthritis and arthralgia occur during the second, or subacute, phase, which is characterized by gradual subsiding of fever, thrombocytosis, and desquamation of the palms and soles. Third is a convalescent phase where children continue to recover and all laboratory studies normalize but aneurysms of the coronary arteries may continue to enlarge (48). Although this disease appears to be benign and self-limiting in most instances, coronary artery aneurysms or vascular ectasia develop in 20% to 25% of untreated Kawasaki patients and can lead to serious morbidity and even death (48,49). The cardiac lesions in Kawasaki disease occur in different stages, developing from an acute perivasculitis and vasculitis of the microvessels and small arteries to a panvasculitis of the coronary arteries with aneurysms and thrombosis. The late phase of development is characterized by myocardial scarring with severe stenosis in the major coronary arteries (47). A specific diagnostic test, however, does not exit. Thus, the diagnosis of Kawasaki disease is based on the presence of a fever for at least 5 days as well as the presence at least four of the five classic clinical features: (1) bilateral nonexudative bulbar conjunctival injection, (2) unilateral nonsuppurative cervical adenopathy, (3) oral or lip erythema, (4) edema or erythema of hands and feet, and (5) a polymorphous erythematous rash. Echocardiography is useful during the acute and subacute phase of the disease for the assessment of ventricular function and to delineate coronary aneurysms or ectasia. Up to 40% of untreated patients with Kawasaki disease have echocardiographically documented coronary artery dilatation and aneurysms in the third or convalescence phase of their disease (50). Cardiac involvement may cause different cardiac events, from silent chest pain to acute myocardial ischemia or sudden death due to myocardial infarction from occlusive coronary artery disease. Incidence, onset, and the time course of stenosis formation in the aneurysm are affected by various factors, such as the diameter of the aneurysm and the location and type of coronary arteries involved.

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It is therefore critical to recognize aneurysms in Kawasaki disease to determine effective early therapy and to improve prognosis. Two-dimensional echocardiography can detect coronary aneurysms. However, this method is not as effective for detecting coronary stenosis. Coronary angiography is an accurate method for assessing large and medium-sized coronary arteries but has little value in detecting microangiopathy (51). Furthermore, angiography is an invasive and potentially harmful procedure, with a nontrivial amount of radiation exposure that cannot be repeated often, especially in the pediatric population. Information about myocardial perfusion and regions of ischemia is necessary to make clinical decisions and to evaluate the prognosis. In the past, children with a previous history of Kawasaki disease but no detectable angiographic coronary lesions during the acute and subacute phase were thought not to be at risk for myocardial ischemia. More recent studies have demonstrated the presence of reversible myocardial perfusion defects in children with angiographically normal coronary arteries. The clinical significance of these findings remains to be fully addressed (52). An alteration of the coronary microcirculation, possibly the result of a previous inflammatory process, has been suggested as a cause of the abnormalities in myocardial perfusion. Different authors have reported an abnormal hyperemic MBF and an impaired coronary flow reserve in patients with a previous history of Kawasaki disease but normal epicardial coronary arteries, after an adenosine-induced hyperemia PET study (53,54). These microcirculatory abnormalities, which could represent a risk factor for the development of atherosclerosis in adulthood, may correspond to an endothelium-dependent dysfunction. Furuyama et al. (55) described an impaired MBF response to the cold-pressor testing using 15 O-H2O PET in patients with Kawasaki disease, when compared to normal controls, suggesting an intimal hypertrophy in these patients (55). An abnormal endothelium-dependent vasodilation in the brachial artery of patients with a previous history of Kawasaki disease seems to confirm that endothelial dysfunction may at least contribute to the microcirculatory changes responsible for myocardial perfusion alterations. Positron emission tomography has been used in patients with Kawasaki and demonstrable coronary aneurysms as well to demonstrate an impaired hyperemic and coronary flow reserve, as reported by Ohmochi et al. (56). Interestingly, Yoshibayashi et al. (57) have correlated the presence of ischemic myocardial injury with the appearance of abnormal Q waves in the electrocardiogram (ECG) when compared to a 13N-ammonia and 18F-FDG PET. They reported that the presence of abnormal Q waves is a reliable clue to the presence of ischemic myocardial injury, whereas metabolic PET imaging showed viable myocardial tissue in those areas with an abnormal Q wave (57). Monitoring the response to different therapies is another area of application of PET imaging. Hwang et al. (58) reported that the incidence of perfusion and metabolic PET abnormalities was reduced in patients in the convalescent stage of Kawasaki disease when they were

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treated with a 5-day dose of intravenous (IV) immunoglobulin, compared to those who received only a single dose of IV immunoglobulin. Coronary arteries that have been previously aneurysmal have an abnormal response to vasodilators in Kawasaki patients. Intravascular ultrasound imaging of the coronary arteries demonstrated increased intimal thickening in many regions of resolved aneurysms but normal intimal thickness in those patients with Kawasaki disease and no previous history of a coronary artery lesion (59). These findings support the continuous surveillance of all children with a history of Kawasaki disease regardless of coronary artery status. Approximately 50% of patients who had coronary aneurysms show regression on follow-up coronary angiography (60). However, these angiographically normal vessels showed intimal thickening and endothelial dysfunction similar to that observed in early atherosclerotic lesions. Because these patients should be followed carefully to monitor potential late effects of Kawasaki disease in the coronary circulation, periodical PET measurement of MBF seems very appropriate in this particular setting. It has been reported that abnormal myocardial perfusion is present long-term after the resolution of complicated Kawasaki disease, and that unfavorable perfusion response to pharmacologic stress was coupled with an abnormal regional contractility. On the other hand, however, enhanced perfusion correlated poorly with segmental contractility response (52). Therefore, even if these abnormalities are modest and do not seem to diminish exercise performance in these patients, these findings may have implications later in life when other coronary risk factors may potentiate the development of coronary artery disease during adulthood. Cardiac Transplant Vasculopathy Allograft vasculopathy has emerged as the most important limiting factor for long-term survival and is the leading cause of death 1 year after transplantation. At 10 years after transplantation, as many as 20% of recipients have developed significant allograft vasculopathy. Because the donor heart is denervated, children with graft vasculopathy rarely present with angina. They may have atypical angina such as shoulder or back pain or, more frequently, abdominal pain. They may also present with syncope or sudden death. Several studies have demonstrated the diffuse nature of cardiac allograft vasculopathy, which affects the major epicardial vessels along their entire length from the base of the heart to the apex and the epicardial and intramyocardial branches (61). Available studies suggest that graft vasculopathy has a mixed etiology, based on the varied patterns of vascular disease seen by coronary angiography, that is, either diffuse and circumferential narrowing in the distal parts of the coronary arteries or focal segmental disorder in the middle and proximal branches similar to atherosclerosis. Major histologic findings include intact internal elastic lamina; rarely, calcification; occasionally, a low grade of vasculitis; and a tendency for the disease to progress rapidly (62). Although treatment of transplant vasculopathy is complex, several studies have showed

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that focal lesions have been treated successfully with percutaneous transluminal coronary angioplasty (63). On the other hand, the results of coronary artery bypass surgery have not been so successful, leaving only retransplantation as an alternative (64). Annual coronary angiography and intravascular ultrasound have been used to detect coronary involvement and to assess the development and progression of this disease. These techniques are invasive and not event-free with a potential harmful effect, especially in the pediatric population. Therefore, it is paramount to introduce a noninvasive test to detect the progression of the disease and to predict future long-term outcome and cardiac events. Several studies have demonstrated in the adult population that technetium-based myocardial perfusion studies are useful to screen for significant coronary artery disease in the transplant vasculopathy (65). Additionally, they provide incremental data for the prediction of cardiac death in heart transplant patients, as described by Elhendy et al. (66). Cardiac PET studies have shown a decreased coronary flow reserve in adult cardiac allografts after pharmacologically stress-induced hyperemia with dipyridamole (67,68). In addition to a decreased exercise capacity, PET imaging has described an incomplete reinnervation in the transplanted adult heart (69). Cardiomyopathies of Diverse Origin Cardiac PET has proven to be of utility in monitoring response to therapy and in predicting potential long-term outcome by measuring MBF after corrective surgery in specific cardiomyopathies. Donnelly et al. (70) reported on a small group of patients with a hypoplastic left heart syndrome assessed after corrective surgery, and found that coronary flow reserve was reduced due to a higher resting MBF. Also, longterm survivors of the Mustard operation have shown a high prevalence of right ventricular dysfunction. In these patients a decreased coronary flow reserve, as reported by Singh et al. (71), may help explain the systemic ventricular dysfunction they suffer. The long-term outcome of circulation driven by a single ventricular chamber remains a matter of concern as multiple sequelae, such as thromboembolic complications, ventricular dysfunction, arrhythmias, and reduced exercise capacity, can arise from subtle but continuous circulatory changes (72). Thus, coronary artery blood flow may be compromised if the ventricular mass increases significantly to reduce systolic and diastolic function. Hauser el al. (73) has reported an impaired stress MBF, impaired coronary flow reserve, and an elevated vascular resistance after vasodilation in patients with Fontan-like operations. In the cardiomyopathy of Duchenne and Becker muscular dystrophies, studies at necropsy have shown that the posterolateral wall of the left ventricle is the first myocardial area suffering from dystrophy even in the absence of small vessel coronary artery disease in these regions. Perloff et al. (74) have reported areas of myocardial hibernation, identified by perfusion and metabolic PET imaging, in the

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lateral and posterolateral wall in a group of patients with Duchenne dystrophy. Very low coronary flow reserve values measured with PET are reported in neonates with surgically treated congenital heart disease (75). Because the chronically dilated extramural coronary arteries in cyanotic congenital heart disease have a limited capacity to dilate further and because myocardial oxygen extraction is inherently maximal, the potential oxygen debt incurred by systemic arterial hypoxemia may be inadequately met. Basal coronary flow as determined by 13N-ammonia PET was increased to the same degree in the right ventricular and left ventricular free walls and in the ventricular septum, but hyperemic perfusion, coronary vascular resistance, and flow reserve were normal in each of the three regions of interest. Although these studies were not designed to determine the mechanism(s) by which flow reserve is preserved in the face of increased basal coronary flow, the results may suggest remodeling of the intramyocardial coronary microcirculation and vasculogenesis in response to hypoxemic stimulation as potential causes for explaining the neonatal myocardial adaptation to different conditions.

Future Directions Although current cardiac PET clinical applications in pediatrics are still limited, the greater availability of PET systems and infrastructure along with greater knowledge of its capabilities by the pediatric medical community are allowing PET imaging to become more than a tool for the noninvasive assessment of myocardial perfusion and glucose metabolism. It promises to have great potential for applications such as in vivo assessment of cardiac cellular metabolism and receptor function and gene expression. Finally, the potential of combined multimodality imaging, represented by PET–computed tomography (CT) imaging, may provide in the near future real-time assessment of function and structure of the diseased pediatric heart.

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M. Hernandez-Pampaloni 25. Buck A, et al. Effect of carbon-11–acetate recirculation on estimates of myocardial oxygen consumption by PET. J Nucl Med 1991;32(10):1950– 1957. 26. Wolpers HG, et al. Assessment of myocardial viability by use of 11C-acetate and positron emission tomography. Threshold criteria of reversible dysfunction. Circulation 1997;95(6):1417–1424. 27. Armbrecht JJ, et al. Regional myocardial oxygen consumption determined noninvasively in humans with (1–11C)acetate and dynamic positron tomography. Circulation 1989;80(4):863–872. 28. Opie LH. Effects of regional ischemia on metabolism of glucose and fatty acids. Relative rates of aerobic and anaerobic energy production during myocardial infarction and comparison with effects of anoxia. Circ Res 1976;38(5 Suppl 1):I52–74. 29. Brosius FC 3rd, et al. Persistent myocardial ischemia increases GLUT1 glucose transporter expression in both ischemic and non-ischemic heart regions. J Mol Cell Cardiol 1997;29(6):1675–1685. 30. Sivitz WI, et al. Pretranslational regulation of two cardiac glucose transporters in rats exposed to hypobaric hypoxia. Am J Physiol 1992;263(3 pt 1): E562–569. 31. Krivokapich J, et al. Fluorodeoxyglucose rate constants, lumped constant, and glucose metabolic rate in rabbit heart. Am J Physiol 1987;252(4 pt 2): H777–787. 32. Laubenbacher C, et al. An automated analysis program for the evaluation of cardiac PET studies: initial results in the detection and localization of coronary artery disease using nitrogen-13–ammonia. J Nucl Med 1993;34(6): 968–978. 33. Tillisch J, et al. Reversibility of cardiac wall-motion abnormalities predicted by positron tomography. N Engl J Med 1986;314(14):884–888. 34. Knuuti MJ, et al. Myocardial viability: fluorine-18-deoxyglucose positron emission tomography in prediction of wall motion recovery after revascularization. Am Heart J 1994;127(4 Pt 1):785–796. 35. Kuhle WG, et al. Quantification of regional myocardial blood flow using 13N-ammonia and reoriented dynamic positron emission tomographic imaging. Circulation 1992;86(3):1004–1017. 36. American Academy of Pediatrics Committee on Drugs: Guidelines for monitoring and management of pediatric patients during and after sedation for diagnostic and therapeutic procedures. Pediatrics 1992;89(6 pt 1): 1110–1115. 37. Practice guidelines for sedation and analgesia by non-anesthesiologists. Anesthesiology 2002;96(4):1004–1017. 38. Tanel RE, et al. Coronary artery abnormalities detected at cardiac catheterization following the arterial switch operation for transposition of the great arteries. Am J Cardiol 1995;76(3):153–157. 39. Wernovsky G, et al. Factors influencing early and late outcome of the arterial switch operation for transposition of the great arteries. J Thorac Cardiovasc Surg 1995;109(2):289–301; discussion 301–302. 40. Weindling SN, et al. Myocardial perfusion, function and exercise tolerance after the arterial switch operation. J Am Coll Cardiol 1994;23(2):424–433. 41. Bengel FM, et al. Myocardial blood flow and coronary flow reserve late after anatomical correction of transposition of the great arteries. J Am Coll Cardiol 1998;32(7):1955–1961. 42. Yates RW, et al. Evaluation of myocardial perfusion using positron emission tomography in infants following a neonatal arterial switch operation. Pediatr Cardiol 2000;21(2):111–118.

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M. Hernandez-Pampaloni 59. Dahdah NS, et al. Segmental myocardial contractility versus perfusion in Kawasaki disease with coronary arterial aneurysm. Am J Cardiol 1999; 83(1):48–51. 60. Kato H, et al. Long-term consequences of Kawasaki disease. A 10- to 21year follow-up study of 594 patients. Circulation 1996;94(6):1379–1385. 61. Billingham ME. Histopathology of graft coronary disease. J Heart Lung Transplant 1992;11(3 pt 2):S38–44. 62. Grant SC, Brooks NH, Levy RD. Routine coronary angiography after heart transplantation. Heart 1997;78(2):101–102. 63. Wong PM, et al. Efficacy of coronary stenting in the management of cardiac allograft vasculopathy. Am J Cardiol 1998;82(2):239–241. 64. Halle AA 3rd, et al. Coronary angioplasty, atherectomy and bypass surgery in cardiac transplant recipients. J Am Coll Cardiol 1995;26(1):120–128. 65. Carlsen J, et al. Myocardial perfusion scintigraphy as a screening method for significant coronary artery stenosis in cardiac transplant recipients. J Heart Lung Transplant 2000;19(9):873–878. 66. Elhendy A, et al. Prediction of mortality in heart transplant recipients by stress technetium-99m tetrofosmin myocardial perfusion imaging. Am J Cardiol 2002;89(8):964–968. 67. Zhao XM, et al. Nitrogen-13–ammonia and PET to detect allograft coronary artery disease after heart transplantation: comparison with coronary angiography. J Nucl Med 1995;36(6):982–987. 68. Preumont N, et al. Early alterations of myocardial blood flow reserve in heart transplant recipients with angiographically normal coronary arteries. J Heart Lung Transplant 2000;19(6):538–545. 69. Uberfuhr P, et al. Incomplete sympathic reinnervation of the orthotopically transplanted human heart: observation up to 13 years after heart transplantation. Eur J Cardiothorac Surg 2000;17(2):161–168. 70. Donnelly JP, et al. Resting coronary flow and coronary flow reserve in human infants after repair or palliation of congenital heart defects as measured by positron emission tomography. J Thorac Cardiovasc Surg 1998;115(1):103–110. 71. Singh TP, et al. Myocardial flow reserve in patients with a systemic right ventricle after atrial switch repair. J Am Coll Cardiol 2001;37(8):2120–2125. 72. Fishberger SB, et al. Factors that influence the development of atrial flutter after the Fontan operation. J Thorac Cardiovasc Surg 1997;113(1):80–86. 73. Hauser M, et al. Myocardial perfusion and coronary flow reserve assessed by positron emission tomography in patients after Fontan-like operations. Pediatr Cardiol 2003;24(4):386–392. 74. Perloff JK, Henze E, Schelbert HR. Alterations in regional myocardial metabolism, perfusion, and wall motion in Duchenne muscular dystrophy studied by radionuclide imaging. Circulation 1984;69(1):33–42. 75. Oskarsson G. Coronary flow and flow reserve in children. Acta Paediatr Suppl 2004;93(446):20–25.

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23 Fever of Unknown Origin Hongming Zhuang and Ghassan El-Haddad

Definition and Classification General Criteria The original criteria for fever of unknown origin (FUO) as set forth in 1961 by Petersdorf and Beeson were fever higher than 38.3°C on several occasions of at least 3 weeks’ duration and uncertain diagnosis after 1 week of study in the hospital (1). This definition was later revised, and the criterion of 1 week of hospitalization has been replaced by 3 days of hospitalization or three outpatient visits (2,3). In addition to the previously described classic FUO, additional categories have been added: nosocomial, neutropenic, and HIV-associated FUO (3,4). Nosocomial FUO refers to the hospitalized patient with a temperature of ≥38.3°C (≥101°F) on several occasions, who is receiving acute care, and in whom infection was not manifest or incubating on admission. The diagnosis of nosocomial FUO is made after 3 days of illness under investigation, including at least 2 days’ incubation of cultures. Examples of diseases causing nosocomial FUO are septic thrombophlebitis, sinusitis, Clostridium difficile colitis, and drug fever. Neutropenic FUO includes patients with fever of ≥38.3°C (≥101°F) on several occasions, a neutrophil count either 90% of connective tissue diseases that cause FUO, followed by SLE and other types of vasculitis (6,8,9,17). Some autoimmune diseases that occur exclusively in adults are adult Still’s disease, giant cell arteritis, and polymyalgia rheumatica. Temporal arteritis, polymyalgia rheumatica, sarcoidosis, rheumatoid arthritis, and Wegener’s granulomatosis account for 25% to 30% of all FUOs in patients over 65 years of age (15). Lymphoma and leukemia are the two most common malignancies presenting as FUO in children. The frequency of neoplasms decreased

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Table 23.1. Etiologies to be considered in children with fever of unknown origin (FUO) Infections Generalized Hepatitis viruses Cytomegalovirus HIV EBV Cat-scratch disease Tuberculosis (TB) Brucellosis Leptospirosis Malaria Salmomellosis Toxoplasmosis Tularemia Localized Arthritis Osteomyelitis Intraabdominal abscesses Upper respiratory tract infections (URI) Urinary tract infection (UTI)

Noninfectious inflammatory diseases JRA SLE Crohn’s disease Ulcerative colitis Sarcoidosis Kawasaki’s disease Neoplasms Non-Hodgkin’s lymphoma Hodgkin’s disease Leukemia Renal cell carcinoma Hepatoma, Neuroblastoma Wilms’ tumor

Miscellaneous causes Central nervous system dysfunction Diabetes Insipidus Drug fever Familial dysautonomia (Riley-Day syndrome) Factitious fever Thyroiditis Periodic fevers (e.g. familial Mediterranean fever) Infantile cortical hyperostosis Pancreatitis Hypothalamic-central fever Thrombophlebitis Pulmonary embolism Serum sickness Factitious feverEctodermal dysplasia

in two series (12,18), which was attributed to improved diagnostic imaging techniques. Despite extensive investigations, 10% to 20% of FUO cases in children remain undiagnosed.

Diagnosis Despite the fact that most children with FUO have a self-limited disease, it is still a very serious clinical problem, with mortality reaching 6% to 9% in two series of children with FUO (8,9). The diagnostic approach in children with FUO starts with a thorough history and physical examination, supplemented by laboratory and radiographic tests. Repeated histories and physical examination are important to better elucidate the etiology of FUO. The age of the patient, history of exposure to wild or domestic animals, history of unusual dietary habits or travel, medication history, and ethnic background are very helpful in evaluating FUO. After the screening laboratory and radiographic tests, additional tests should be guided by the history and physical examination.

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Radiographic Evaluation of Children with FUO After obtaining a regular chest radiograph, further radiographic examination of specific areas such as the nasal sinuses, mastoids, and gastrointestinal (GI) tract should be performed following special indications. Inflammatory bowel disease should be excluded in children with abdominal complaints, persistent fever, elevated erythrocyte sedimentation rate (ESR), anorexia, and weight loss. Finding a cost-effective diagnostic imaging procedure is challenging for the clinicians. Echocardiograms are useful to evaluate the heart when suspecting infective endocarditis (19). Ultrasonography (US) is often used to investigate fluid collections, abscesses (20,21), and thrombophlebitis (22). Computed tomography (CT) or magnetic resonance imaging (MRI) is helpful in the detection of neoplasms and abscesses in the abdomen and in the investigation of lesions in the head, neck, and chest (23–28), as well as for osteomyelitis (29). Magnetic resonance imaging is rarely used in the initial evaluation of FUO except in certain cases such as spinal epidural abscesses (30). Laparotomy has been nearly replaced by noninvasive imaging techniques, especially in the search for occult abscesses or hematomas in patients with FUO. However, laparotomy is very helpful when noninvasive imaging measures are nondiagnostic and CT- or ultrasound-guided aspiration or biopsy fails to make the diagnosis (31). Radionuclide Scans Gallium-67– and indium-111–labeled leukocytes have a higher overall yield than CT or US in diagnosing FUO because the images cover the whole body (32,33). In patients with FUO, gallium 67 is useful for the detection of malignancies and of granulomatous and inflammatory disorders (34), whereas indium-111–labeled leukocytes are more useful for detecting localized infectious and inflammatory processes (35). Different technetium-99m (99mTc)-labeled compounds are being studied for potential clinical use in patients with FUO, such as 99mTc-hexamethylpropylene-amine-oxime (HMPAO)-labeled leukocytes (36), 99mTc-ciprofloxacin (37), and 99mTc-labeled monoclonal antibodies (38,39). FDG-PET Scan Mechanisms of FDG Uptake by the Cells Currently, 18-fluoro-2-deoxyglucose (FDG) is the most clinically used radiotracer in positron emission tomography (PET). It competes with glucose for transport into the cell and for enzymatic phosphorylation by hexokinase, which enables us to image glucose metabolism in the body. Once FDG enters the cell, it is phosphorylated by hexokinase and trapped inside, which leads to an increase in its concentration with time (40). The uptake of FDG by the malignant cells is directly proportional to glucose metabolism (41). There is enhanced glycolysis in malignant

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cells, which is related to high intracellular enzyme levels of hexokinase (42) and increased expression of surface glucose transporter proteins (GLUT) (43). Infectious, inflammatory, and granulomatous diseases have increased glycolysis, which makes them readily visualized by FDGPET scanning (44). Glycolysis is enhanced in inflammatory cells when the latter are stimulated, and this includes neutrophils, monocytemacrophages, and lymphocytes (45–48). This has been mainly attributed to a high concentration of GLUT and a high affinity of these transporters for FDG. Especially, many investigations have demonstrated that there are increased levels of GLUT on the inflammatory cells when they are activated by inflammatory signals (46,47,49). Intratumoral inflammatory reactions also have a high rate of glycolysis (50,51).

Rationale for the Use of FDG-PET in FUO The fact that FDG is not a tumor-specific substance can be exploited in a positive matter in the setting of FUO because infections, inflammations, and malignancies account for the great majority of FUO cases. Fluorodeoxyglucose-PET has proven to be a very accurate modality for the detection of a large number of malignancies (52). Conventional anatomic imaging modalities rely on size as a criterion to distinguish between malignant and benign diseases; FDG-PET reflects the biochemical alterations within tumors, facilitating a functional assessment of malignancies. This has proven to provide a very accurate assessment of solitary pulmonary nodules, lymphoma, non–small cell lung cancer, colorectal cancer, malignant melanoma, head and neck cancers, and breast cancers (52). The success of PET is not limited to the staging of malignancies but goes beyond that to the accurate assessment of restaging and evaluation of response to therapy. This has been particularly proven in lymphoma in the adult (53,54) and pediatric (55) populations, and it has a direct impact on the management of patients with FUO because lymphoma accounts for the majority of cancers causing FUO. Fluorodeoxyglucose-PET is able to differentiate necrotic tissue from viable tumor and has proven its superiority to other imaging techniques in the initial staging of lymphoma, in monitoring response to therapy, and in detecting residual tumor (53,54). Many metabolically active infectious and inflammatory disorders can be readily visualized by FDG-PET scanning (56,57) (Table 23.2). Fluorodeoxyglucose-PET has a high accuracy in detecting chronic osteomyelitis (58), especially in the central skeleton, which was found to be superior to antigranulocyte antibody scintigraphy (59,60) and to indium-111–labeled leukocytes (61). Although CT and MRI provide excellent anatomic details, they have limited capacity to differentiate postsurgical changes from infection, and, in contrast to FDG-PET, they are hindered by metal implants (62,63). Fluorodeoxyglucose-PET can differentiate between normal bone

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Table 23.2. Common causes of FUO reportedly detected by FDG-PET Infections Subphrenic abscess Pneumonia Osteomyelitis Vascular graft infection Tuberculosis Sinusitis Mastoiditis

Inflammatory/granulomatous Takayasu’s arteritis Rheumatoid arthritis Wegener’s granulomatosis Sarcoidosis Thyroiditis Enterocolitis Myositis Gastritis Giant cell arteritis

Neoplasms Hodgkin’s disease Non-Hodgkin’s lymphoma Colon carcinoma Renal cell carcinoma Sarcoma Pheochromocytoma

healing following a fracture or surgical intervention and osteomyelitis or malignancy (64,65). In patients with prostheses, FDG-PET can assess the presence of a superimposed infection, especially in hip prostheses and, to a lesser extent, in knee prostheses (66). FluorodeoxyglucosePET can be used to diagnose infections related to diabetes, especially in the evaluation of the diabetic foot (67). Human immunodeficiency virus (HIV)-positive patients constitute a special group of patients because they are prone to opportunistic infections and malignancies, especially lymphoma. In a report on HIV-positive patients with FUO, FDG-PET had a sensitivity of 92% and a specificity of 94% for localizing a focal pathology that needed treatment (68). Fluorodeoxyglucose-PET was able to differentiate lymphoma from nonmalignant lesions in the central nervous system in HIV-positive patients (69). Although FDG-PET cannot clearly distinguish between granulomatous diseases such as sarcoidosis and lymphoma, it can localize the active lesions (70,71), which can be biopsied for a timely and minimally invasive diagnosis. The early diagnosis of vasculitis, especially large-vessel vasculitis, prevents progression to the occlusive phase of the disease. In this regard, FDG-PET has demonstrated high specificity and high sensitivity to detect and assess the activity of large-vessel vasculitis (72,73). It can noninvasively detect and quantitatively assess the disease activity in inflammatory bowel disease (74,75). Fluorodeoxyglucose uptake in the synovium measured using the standard uptake values (SUVs) facilitates the quantitative assessment of synovial activity (76), which has been particularly helpful in assessing the disease activity in patients with rheumatoid arthritis (77). The increase in SUV and the number of PET-positive joints correlated with swelling and tenderness of the joints, ultrasonography, synovial thickness, and inflammatory serum markers (ESR and C-reactive protein). This facilitates the measurement of disease activity in the joints of patients with rheumatologic diseases. Other infectious or inflammatory process that can be visualized with FDG-PET are thrombophlebitis (78,79), infected implantable devices (80), and pleural diseases (81).

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Advantages of FDG-PET over Other Nuclear Medicine Techniques Currently, gallium-67 scanning is the most commonly used radiotracer for the evaluation of FUO (32). However, FDG-PET has many advantages over conventional nuclear medicine techniques. Fluorodeoxyglucose offers a better tracer kinetic, a favorable 110-minute half-life, better spatial resolution (±5 to 8 mm resolution for PET vs. 10 to 15 mm for single photon emission computed tomography, SPECT), better lesion-to-background ratio (82), low dose to the patient, and the possibility for quantification decreasing the variability between readers. To date there have been no reported side effects from the injection of FDG. Whole-body FDG-PET scanning is completed approximately 2 hours from the injection, which results in earlier reporting than with other radiotracers (83). An important safety factor is that, in contrast to labeled leukocytes, in FDG-PET there is no handling of blood products. Fluorodeoxyglucose-PET is more sensitive in chronic, low-grade infections, has high accuracy in the central skeleton, and a high interobserver agreement (59,84,85). Another major advantage of FDG-PET over gallium in the evaluation of FUO patients is the ability to visualize and assess the degree of activity in a variety of inflammatory vessel diseases (83). It has been reported that FDG-PET can clearly visualize sarcoid lesions in the lungs and brain when concurrent gallium scans are negative (86). Advantages of FDG-PET Over Anatomic Imaging Timely identification and localization of the source of FUO is critical for the management of patients. Therefore, FDG-PET scanning is very helpful in this regard because it can detect early changes at the molecular level before they become apparent on anatomic imaging. Fluorodeoxyglucose-PET images the whole body in one study. Posttherapy tissue changes such as scarring, edema, and necrosis may alter the identification of recurrent tumor with anatomic imaging. Regardless of anatomic changes after chemotherapy and radiation therapy, FDG-PET can detect residual disease and has a high negative predictive value for viable disease in a residual anatomic abnormality, reaching 97% in some cases (87). Therefore, equivocal radiographic findings can be accurately characterized with FDG-PET. There is also increasing concern about the risk of radiation (88), radiocontrast-induced nephropathy (89), and allergic reactions (90) to patients imaged with CT. Furthermore, FDG-PET is able to detect early inflammatory and infectious lesions when anatomic imaging modalities reveal no abnormalities (91). FDG-PET and Biopsy As opposed to the other noninvasive diagnostic approaches in FUO, biopsy is a directed invasive intervention, which is often required to make a diagnosis. The most common biopsies performed in an FUO scenario are bone marrow, liver, lymph node, temporal artery, pleura, and pericardium. However, biopsy has spatial limitations, and a negative biopsy result may well be a false-negative finding due to sampling

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errors. The combination of anatomic imaging and FDG-PET either through a software fusion or a combined PET-CT scanne leads to better localization of functional abnormalities. The registration of anatomic and functional images can be used to guide biopsies to the metabolically active area (92), which can increase the yield of this approach and decrease the need for unnecessary procedures. Considerations for Accurate Reading of FDG-PET When searching for the source of FUO, certain areas of the body can sometimes be difficult to evaluate because of normally high FDG uptake. The kidneys excrete FDG; therefore, there is intense FDG activity in the renal collecting systems, ureters, and bladder. There is also high FDG uptake in the brain and myocardium. Fluorodeoxyglucose activity in the bowel can be variably intense in the adult population (Fig. 23.1), which can decrease the accuracy of FDG-PET in the evaluation of the abdomen. However, FDG-PET can play a major role in the pediatric population because there is usually low FDG activity in the bowel (Fig. 23.2) (57). There is also physiologic activity in the thymus of children and young adults, which usually looks like an inverted V

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Figure 23.2. Normal FDG-PET scan of an 11–year-old boy with a history of Hodgkin’s disease. There is a faint activity in the bowel.

(Fig. 23.3) (93). Therefore, accurate interpretation of FDG-PET images requires optimal knowledge of the normal distribution of FDG throughout the anatomic structures of the body and the variations that might occur with age (93). Certain tumors cannot be easily detected with FDG-PET because of low FDG uptake, such as in hepatocellular carcinoma (94) or certain types of pancreatic tumors.(95) Because of the limited spatial resolution of PET (96), it is also difficult to detect low-grade tumors (e.g., cartilaginous tumors) (97), small lung nodules, and brain metastases (98). Although there has been a report of intra-vascular lymphomatosis presenting as fever of unknown origin (99), FDG-PET remains less effective in the detection of small-vessel disease. Because FDG follows a similar pathway as glucose, a normalization of blood sugar level is a must in order not to miss any active malignant lesions because of suboptimal image quality (100). However, it is reported that the serum glucose levels do not necessarily affect the accuracy of FDG-PET when inflammatory and infectious lesion is evaluated (101).

Studies Regarding FDG-PET and FUO There have been a limited number of prospective studies regarding FDG-PET scan and FUO. The percentage of FDG-PET scans helpful in

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the diagnosis of FUO as reported in the literature ranged from 37% to 69% (83,102–106). This variation is attributed to different factors, including a slightly different definition of FUO, a wide array of heterogeneous disorders, variable FDG-PET techniques, and no structured diagnostic protocol. However, the contributory effect of FDG-PET in the diagnosis of FUO was found to be higher than gallium scintigraphy (25%) (83). Fluorodeoxyglucose-PET was more helpful in the diagnostic process of patients with a suspected focal infection or localized inflammation than in FUO (104). Only one study found that indium111–labeled granulocyte scintigraphy had a superior diagnostic performance compared to FDG-PET in the evaluation of FUO (106), but in the 19 patients studied, only one patient was diagnosed with malignancy (Hodgkin’s disease). Our Experience with FDG-PET We retrospectively reviewed 30 FDG-PET scans of 30 patients (aged 13 to 73 years) who were evaluated at our institution for FUO during the period between 1999 and 2004. Clinical follow-up, which included subsequent conventional imaging studies and/or pathology results, was compared to the FDG-PET scan results. Fluorodeoxyglucose-PET contributed to the diagnosis of 71% of the cases. The causes of fever detected by FDG-PET included pneumonia, non-Hodgkin’s lymphoma (Fig. 23.4), Hodgkin’s disease (Fig. 23.5), Crohn’s disease

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Figure 23.3. Normal FDG uptake is seen in the thymus of a 10–year-old patient.

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Figure 23.4. Intense FDG uptake is seen in the spleen, which is markedly enlarged, and two foci of abnormal uptake are visible in the upper abdomen, representing lymphadenopathy. The patient was diagnosed with non-Hodgkin’s lymphoma.

(Fig. 23.6), surgical wound infection, infected liver cysts, leukemia, and metastatic renal cell carcinoma (Fig. 23.7). Fluorodeoxyglucose-PET was falsely negative in three cases of colitis, peritonitis (Fig. 23.8), and rejected renal transplant. Two FDG-PET scans were falsely positive in two patients with suspected abnormal activity in the abdomen; one of them had an eventual diagnosis of endocarditis.

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Figure 23.5. Abnormal FDG uptake is seen in the bone marrow, as well as in supraclavicular and mediastinal lymph nodes of a patient with FUO. The patient was diagnosed with Hodgkin’s disease.

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Figure 23.6. Diffuse FDG activity in the bowel. Although this pattern can be seen in normal adult patients, this finding was the only suspicious source of FUO in this patient, with a history of renal transplant. Subsequent colonoscopies and bone marrow biopsies were negative. The patient underwent a laparotomy; after segmental resection of the terminal ileum and cecum, he was diagnosed with Crohn’s disease.

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Figure 23.7. FDG-PET scan (coronal images) performed on a 13–year-old boy who underwent bilateral nephrectomies and renal transplant for polycystic kidney disease, after the patient developed a fever of unknown origin. Two foci of abnormal FDG uptake were noted in the left inguinal and in the portahepatic regions. There was no evidence of abnormal uptake in the transplanted kidney. Following biopsies, the patient was diagnosed with renal cell carcinoma in the transplanted kidney, which was removed.

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Figure 23.8. Coronal FDG-PET images of a 44–year-old patient who had a history of liver transplant, presenting with marked abdominal and pelvic ascites. There is a large photopenic area in the abdomen corresponding to the abdominal fluid but no definite evidence of a suspected source of FUO. The patient underwent a paracentesis and was diagnosed with peritonitis.

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Conclusion Fluorodeoxyglucose-PET is a valuable new imaging technique that has the potential for a major role in patients with FUO. It can detect malignancies as well as infectious and noninfectious inflammatory processes at an early stage of the disease. It has proven its superiority to other currently used conventional nuclear medicine imaging techniques. When ordered early in the diagnostic workup, FDG-PET has the potential to identify the area of abnormal activity where the cause of fever is likely to be found. This adds valuable information that can be used to focus the investigation and to eliminate unnecessary procedures, resulting in better management of the patients.

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Chapter 23 Fever of Unknown Origin 16. Cunha BA. Fever of unknown origin. Infect Dis Clin North Am 1996; 10:111–127. 17. Miller ML, Szer I, Yogev R, et al. Fever of unknown origin. Pediatr Clin North Am 1995;42:999–1015. 18. Iikuni Y, Okada J, Kondo H, et al. Current fever of unknown origin 1982–1992. Intern Med 1994;33:67–73. 19. Hoen B, Beguinot I, Rabaud C, et al. The Duke criteria for diagnosing infective endocarditis are specific: analysis of 100 patients with acute fever or fever of unknown origin. Clin Infect Dis 1996;23:298–302. 20. Carey BM, Williams CE, Arthur RJ. Ultrasound demonstration of pericardial empyema in an infant with pyrexia of undetermined origin. Pediatr Radiol 1988;18:349–350. 21. Picardi M, Morante R, Rotoli B. Ultrasound exploration in the work-up of unexplained fever in the immunocompromized host: preliminary observations. Haematologica 1997;82:455–457. 22. AbuRahma AF, Saiedy S, Robinson PA, et al. Role of venous duplex imaging of the lower extremities in patients with fever of unknown origin. Surgery 1997;121:366–371. 23. Gartner JC Jr. Fever of unknown origin. Adv Pediatr Infect Dis 1992;7: 1–24. 24. Cheng MF, Chiou CC, Hsieh KS. Mastoiditis: a disease often overlooked by pediatricians. J Microbiol Immunol Infect 2000;33:237–240. 25. Picus D, Siegel MJ, Balfe DM. Abdominal computed tomography in children with unexplained prolonged fever. J Comput Assist Tomogr 1984; 8:851–856. 26. de Leon DG, Shifteh S, Cunha BA. FUO due to sarcoidosis-lymphoma syndrome. Heart Lung 2004;33:124–129. 27. Gedalia A, Shetty AK, Ward KJ, et al. Role of MRI in diagnosis of childhood sarcoidosis with fever of unknown origin. J Pediatr Orthop 1997; 17:460–462. 28. Wagner AD, Andresen J, Raum E, et al. Standardised work-up programme for fever of unknown origin and contribution of magnetic resonance imaging for the diagnosis of hidden systemic vasculitis. Ann Rheum Dis 2005;64:105–110. 29. Berendt AR, Lipsky B. Is this bone infected or not? Differentiating neuroosteoarthropathy from osteomyelitis in the diabetic foot. Curr Diab Rep 2004;4:424–429. 30. Bluman EM, Palumbo MA, Lucas PR. Spinal epidural abscess in adults. J Am Acad Orthop Surg 2004;12:155–163. 31. Ozaras R, Celik AD, Zengin K, et al. Is laparotomy necessary in the diagnosis of fever of unknown origin? Acta Chir Belg 2005;105:89–92. 32. Knockaert DC, Mortelmans LA, De Roo MC, et al. Clinical value of gallium-67 scintigraphy in evaluation of fever of unknown origin. Clin Infect Dis 1994;18:601–605. 33. Syrjala MT, Valtonen V, Liewendahl K, et al. Diagnostic significance of indium-111 granulocyte scintigraphy in febrile patients. J Nucl Med 1987;28:155–160. 34. Peters AM. Nuclear medicine imaging in fever of unknown origin. Q J Nucl Med 1999;43:61–73. 35. Kjaer A, Lebech AM. Diagnostic value of (111)In-granulocyte scintigraphy in patients with fever of unknown origin. J Nucl Med 2002;43: 140–144. 36. Peters AM. The utility of [99mTc]HMPAO-leukocytes for imaging infection. Semin Nucl Med 1994;24:110–127.

H. Zhuang and G. El-Haddad 37. Gallowitsch HJ, Heinisch M, Mikosch P, et al. [Tc-99m ciprofloxacin in clinically selected patients for peripheral osteomyelitis, spondylodiscitis and fever of unknown origin–preliminary results]. Nuklearmedizin 2002; 41:30–36. 38. Meller J, Ivancevic V, Conrad M, et al. Clinical value of immunoscintigraphy in patients with fever of unknown origin. J Nucl Med 1998;39: 1248–1253. 39. Maugeri D, Santangelo A, Abbate S, et al. A new method for diagnosing fever of unknown origin (FUO) due to infection of muscular-skeletal system in elderly people: leukoscan Tc-99m labelled scintigraphy. Eur Rev Med Pharmacol Sci 2001;5:123–126. 40. Ak I, Stokkel MP, Pauwels EK. Positron emission tomography with 2–[18F] fluoro-2–deoxy-D-glucose in oncology. Part II. The clinical value in detecting and staging primary tumours. J Cancer Res Clin Oncol 2000;126:560–574. 41. Hawkins RA, Choi Y, Huang SC, et al. Quantitating tumor glucose metabolism with FDG and PET. J Nucl Med 1992;33:339–344. 42. Avril N, Menzel M, Dose J, et al. Glucose metabolism of breast cancer assessed by 18F-FDG PET: histologic and immunohistochemical tissue analysis. J Nucl Med 2001;42:9–16. 43. Warburg O. On the origin of cancer cells. Science 1956;123:309–314. 44. Bakheet SM, Powe J. Benign causes of 18–FDG uptake on whole body imaging. Semin Nucl Med 1998;28:352–358. 45. Chakrabarti R, Jung CY, Lee TP, et al. Changes in glucose transport and transporter isoforms during the activation of human peripheral blood lymphocytes by phytohemagglutinin. J Immunol 1994;152:2660– 2668. 46. Gamelli RL, Liu H, He LK, et al. Augmentations of glucose uptake and glucose transporter-1 in macrophages following thermal injury and sepsis in mice. J Leukoc Biol 1996;59:639–647. 47. Ahmed N, Kansara M, Berridge MV. Acute regulation of glucose transport in a monocyte-macrophage cell line: Glut-3 affinity for glucose is enhanced during the respiratory burst. Biochem J 1997;327(pt 2):369–375. 48. Tan AS, Ahmed N, Berridge MV. Acute regulation of glucose transport after activation of human peripheral blood neutrophils by phorbol myristate acetate, fMLP, and granulocyte-macrophage colony-stimulating factor. Blood 1998;91:649–655. 49. Sorbara LR, Maldarelli F, Chamoun G, et al. Human immunodeficiency virus type 1 infection of H9 cells induces increased glucose transporter expression. J Virol 1996;70:7275–7279. 50. Kubota R, Yamada S, Kubota K, et al. Intratumoral distribution of fluorine-18–fluorodeoxyglucose in vivo: high accumulation in macrophages and granulation tissues studied by microautoradiography. J Nucl Med 1992;11:1972–1980. 51. Brown RS, Leung JY, Fisher SJ, et al. Intratumoral distribution of tritiated fluorodeoxyglucose in breast carcinoma: I. Are inflammatory cells important? J Nucl Med 1995;36:1854–1861. 52. Kostakoglu L, Agress H Jr, Goldsmith SJ. Clinical role of FDG PET in evaluation of cancer patients. Radiographics 2003;23:315–340; quiz 533. 53. Divgi C. Imaging: Staging and evaluation of lymphoma using nuclear medicine. Semin Oncol 2005;32:11–18. 54. Kazama T, Faria SC, Varavithya V, et al. FDG PET in the evaluation of treatment for lymphoma: clinical usefulness and pitfalls. Radiographics 2005;25:191–207.

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Chapter 23 Fever of Unknown Origin 55. Hudson MM, Krasin MJ, Kaste SC. PET imaging in pediatric Hodgkin’s lymphoma. Pediatr Radiol 2004;34:190–198. 56. Zhuang H, Alavi A. 18–fluorodeoxyglucose positron emission tomographic imaging in the detection and monitoring of infection and inflammation. Semin Nucl Med 2002;32:47–59. 57. El-Haddad G, Zhuang H, Gupta N, et al. Evolving role of positron emission tomography in the management of patients with inflammatory and other benign disorders. Semin Nucl Med 2004;34:313– 329. 58. Zhuang H, Duarte PS, Pourdehand M, et al. Exclusion of chronic osteomyelitis with F-18 fluorodeoxyglucose positron emission tomographic imaging. Clin Nucl Med 2000;25:281–284. 59. Guhlmann A, Brecht-Krauss D, Suger G, et al. Fluorine-18–FDG PET and technetium-99m antigranulocyte antibody scintigraphy in chronic osteomyelitis. J Nucl Med 1998;39:2145–2152. 60. Guhlmann A, Brecht-Krauss D, Suger G, et al. Chronic osteomyelitis: detection with FDG PET and correlation with histopathologic findings. Radiology 1998;206:749–754. 61. Meller J, Koster G, Liersch T, et al. Chronic bacterial osteomyelitis: prospective comparison of (18)F-FDG imaging with a dual-head coincidence camera and (111)In-labelled autologous leucocyte scintigraphy. Eur J Nucl Med Mol Imaging 2002;29:53–60. 62. Erdman WA, Tamburro F, Jayson HT, et al. Osteomyelitis: characteristics and pitfalls of diagnosis with MR imaging. Radiology 1991;180:533– 539. 63. Crim JR, Seeger LL. Imaging evaluation of osteomyelitis. Crit Rev Diagn Imaging 1994;35:201–256. 64. Zhuang H, Sam JW, Chacko TK, et al. Rapid normalization of osseous FDG uptake following traumatic or surgical fractures. Eur J Nucl Med Mol Imaging 2003;30:1096–1103. 65. Koort JK, Makinen TJ, Knuuti J, et al. Comparative 18F-FDG PET of experimental Staphylococcus aureus osteomyelitis and normal bone healing. J Nucl Med 2004;45:1406–1411. 66. Zhuang H, Duarte PS, Pourdehnad M, et al. The promising role of 18FFDG PET in detecting infected lower limb prosthesis implants. J Nucl Med 2001;42:44–48. 67. Keidar Z, Militianu D, Melamed E, et al. The diabetic foot: initial experience with 18F-FDG PET/CT. J Nucl Med 2005;46:444–449. 68. O’Doherty MJ, Barrington SF, Campbell M, et al. PET scanning and the human immunodeficiency virus-positive patient. J Nucl Med 1997;38: 1575–1583. 69. Heald AE, Hoffman JM, Bartlett JA, et al. Differentiation of central nervous system lesions in AIDS patients using positron emission tomography (PET). Int J STD AIDS 1996;7:337–346. 70. Dubey N, Miletich RS, Wasay M, et al. Role of fluorodeoxyglucose positron emission tomography in the diagnosis of neurosarcoidosis. J Neurol Sci 2002;205:77–81. 71. Milman N, Mortensen J, Sloth C. Fluorodeoxyglucose PET scan in pulmonary sarcoidosis during treatment with inhaled and oral corticosteroids. Respiration 2003;70:408–413. 72. Walter MA, Melzer RA, Schindler C, et al. The value of [(18)F]FDG-PET in the diagnosis of large-vessel vasculitis and the assessment of activity and extent of disease. Eur J Nucl Med Mol Imaging 2005;(6):674–681.

H. Zhuang and G. El-Haddad 73. Moosig F, Czech N, Mehl C, et al. Correlation between 18–fluorodeoxyglucose accumulation in large vessels and serological markers of inflammation in polymyalgia rheumatica: a quantitative PET study. Ann Rheum Dis 2004;63:870–873. 74. Neurath MF, Vehling D, Schunk K, et al. Noninvasive assessment of Crohn’s disease activity: a comparison of 18F-fluorodeoxyglucose positron emission tomography, hydromagnetic resonance imaging, and granulocyte scintigraphy with labeled antibodies. Am J Gastroenterol 2002; 97:1978–1985. 75. Pio BS, Byrne FR, Aranda R, et al. Noninvasive quantification of bowel inflammation through positron emission tomography imaging of 2–deoxy-2–[18F]fluoro-D-glucose-labeled white blood cells. Mol Imaging Biol 2003;5:271–277. 76. Roivainen A, Parkkola R, Yli-Kerttula T, et al. Use of positron emission tomography with methyl-11C-choline and 2–18F-fluoro-2–deoxy-Dglucose in comparison with magnetic resonance imaging for the assessment of inflammatory proliferation of synovium. Arthritis Rheum 2003; 48:3077–3084. 77. Beckers C, Ribbens C, Andre B, et al. Assessment of disease activity in rheumatoid arthritis with (18)F-FDG PET. J Nucl Med 2004;45:956– 964. 78. Bleeker-Rovers CP, Jager G, Tack CJ, et al. F-18–fluorodeoxyglucose positron emission tomography leading to a diagnosis of septic thrombophlebitis of the portal vein: description of a case history and review of the literature. J Intern Med 2004;255:419–423. 79. Miceli M, Atoui R, Walker R, et al. Diagnosis of deep septic thrombophlebitis in cancer patients by fluorine-18 fluorodeoxyglucose positron emission tomography scanning: a preliminary report. J Clin Oncol 2004; 22:1949–1956. 80. Miceli MH, Jones Jackson LB, Walker RC, et al. Diagnosis of infection of implantable central venous catheters by [18F]fluorodeoxyglucose positron emission tomography. Nucl Med Commun 2004;25:813–818. 81. Duysinx B, Nguyen D, Louis R, et al. Evaluation of pleural disease with 18–fluorodeoxyglucose positron emission tomography imaging. Chest 2004;125:489–493. 82. Sugawara Y, Gutowski TD, Fisher SJ, et al. Uptake of positron emission tomography tracers in experimental bacterial infections: a comparative biodistribution study of radiolabeled FDG, thymidine, L-methionine, 67Ga-citrate, and 125I-HSA. Eur J Nucl Med 1999;26: 333–341. 83. Blockmans D, Knockaert D, Maes A, et al. Clinical value of [(18)F]fluorodeoxyglucose positron emission tomography for patients with fever of unknown origin. Clin Infect Dis 2001;32:191–196. 84. de Winter F, van de Wiele C, Vogelaers D, et al. Fluorine-18 fluorodeoxyglucose-position emission tomography: a highly accurate imaging modality for the diagnosis of chronic musculoskeletal infections. J Bone Joint Surg Am 2001;83–A:651–660. 85. Kalicke T, Schmitz A, Risse JH, et al. Fluorine-18 fluorodeoxyglucose PET in infectious bone diseases: results of histologically confirmed cases. Eur J Nucl Med 2000;27:524–528. 86. Xiu Y, Yu XQ, Cheng E, et al. Sarcoidosis demonstrated by FDG PET imaging with negative findings on gallium scintigraphy. Clin Nucl Med 2005;30:193–195.

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Chapter 23 Fever of Unknown Origin 87. Porceddu SV, Jarmolowski E, Hicks RJ, et al. Utility of positron emission tomography for the detection of disease in residual neck nodes after (chemo)radiotherapy in head and neck cancer. Head Neck 2005;27: 175–181. 88. Buls N, de Mey J, Covens P, et al. Health screening with CT: prospective assessment of radiation dose and associated detriment. JBR-BTR 2005;88: 12–16. 89. Asif A, Epstein M. Prevention of radiocontrast-induced nephropathy. Am J Kidney Dis 2004;44:12–24. 90. Cochran ST. Anaphylactoid reactions to radiocontrast media. Curr Allergy Asthma Rep 2005;5:28–31. 91. Dadparvar S, Anderson GS, Bhargava P, et al. Paraneoplastic encephalitis associated with cystic teratoma is detected by fluorodeoxyglucose positron emission tomography with negative magnetic resonance image findings. Clin Nucl Med 2003;28:893–896. 92. Yap JT, Carney JP, Hall NC, et al. Image-guided cancer therapy using PET/CT. Cancer J 2004;10:221–233. 93. El-Haddad G, Alavi A, Mavi A, et al. Normal variants in [18F]fluorodeoxyglucose PET imaging. Radiol Clin North Am 2004;42: 1063–1081, viii. 94. Torizuka T, Tamaki N, Inokuma T, et al. In vivo assessment of glucose metabolism in hepatocellular carcinoma with FDG-PET. J Nucl Med 1995;36:1811–1817. 95. Delbeke D, Pinson CW. Pancreatic tumors: role of imaging in the diagnosis, staging, and treatment. J Hepatobiliary Pancreat Surg 2004;11: 4–10. 96. Takamochi K, Yoshida J, Murakami K, et al. Pitfalls in lymph node staging with positron emission tomography in non-small cell lung cancer patients. Lung Cancer 2005;47:235–242. 97. Lee FY, Yu J, Chang SS, et al. Diagnostic value and limitations of fluorine18 fluorodeoxyglucose positron emission tomography for cartilaginous tumors of bone. J Bone Joint Surg Am 2004;86–A:2677–2685. 98. Friedman KP, Wahl RL. Clinical use of positron emission tomography in the management of cutaneous melanoma. Semin Nucl Med 2004;34: 242–253. 99. Hoshino A, Kawada E, Ukita T, et al. Usefulness of FDG-PET to diagnose intravascular lymphomatosis presenting as fever of unknown origin. Am J Hematol 2004;76:236–239. 100. Sugawara Y, Braun DK, Kison PV, et al. Rapid detection of human infections with fluorine-18 fluorodeoxyglucose and positron emission tomography: preliminary results. Eur J Nucl Med 1998;25:1238–1243. 101. Zhuang HM, Cortes-Blanco A, Pourdehnad M, et al. Do high glucose levels have differential effect on FDG uptake in inflammatory and malignant disorders? Nucl Med Commun 2001;22:1123–1128. 102. Meller J, Altenvoerde G, Munzel U, et al. Fever of unknown origin: prospective comparison of [18F]FDG imaging with a double-head coincidence camera and gallium-67 citrate SPET. Eur J Nucl Med 2000;27: 1617–1625. 103. Lorenzen J, Buchert R, Bohuslavizki KH. Value of FDG PET in patients with fever of unknown origin. Nucl Med Commun 2001;22:779–783. 104. Bleeker-Rovers CP, de Kleijn EM, Corstens FH, et al. Clinical value of FDG PET in patients with fever of unknown origin and patients suspected of focal infection or inflammation. Eur J Nucl Med Mol Imaging 2004;31: 29–37.

H. Zhuang and G. El-Haddad 105. Buysschaert I, Vanderschueren S, Blockmans D, et al. Contribution of (18)fluoro-deoxyglucose positron emission tomography to the work-up of patients with fever of unknown origin. Eur J Intern Med 2004;15: 151–156. 106. Kjaer A, Lebech AM, Eigtved A, et al. Fever of unknown origin: prospective comparison of diagnostic value of 18F-FDG PET and 111Ingranulocyte scintigraphy. Eur J Nucl Med Mol Imaging 2004;31:622–626.

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Positron emission tomography (PET) with fluorine-18 (18F)-fluoro-2deoxyglucose (FDG) has been proven to be a valuable noninvasive imaging modality for the diagnosis, staging, and monitoring of therapy for various malignancies. In addition, studies are demonstrating the value of FDG-PET for the evaluation of nononcologic conditions. Based on the literature, conditions such as osteomyelitis, fever of unknown origin (FUO), acquired immunodeficiency syndrome (AIDS), vasculitis, and inflammatory bowel disease can be successfully imaged with FDG-PET. With the approval of additional PET radiotracers in the future, there will be more widespread applications of PET for inflammatory and infectious disorders. Unlike anatomic imaging modalities such as computed tomography (CT), magnetic resonance imaging (MRI), and ultrasound, PET is a molecular imaging modality that detects metabolic abnormalities present in the disease before structural abnormalities become evident. In addition to FDG, other radiopharmaceuticals are available for scintigraphic imaging such as technetium-99m (99mTc)-hexamethylpropyleneamine-oxime (HMPAO)-labeled leukocytes, indium-111 (111In)-oxime labeled leukocytes, gallium-67 (67Ga) citrate, 99mTc-labeled antigranulocyte monoclonal antibodies, and 99mTc-labeled immunoglobulins. Advantages of FDG-PET as compared with the aforementioned radiopharmaceuticals for the imaging of inflammation and infection include the ability to provide a result as early as 11/2 to 2 hours after tracer injection, the relatively low radiation dose, and the excellent spatial resolution and lesion-to-background contrast. These advantages contribute to the superior accuracy of FDG-PET for the diagnosis or exclusion of infections.

Clinical Applications of FDG-PET The specific clinical applications of FDG-PET are as follows: 1. Osteomyelitis 2. Fever of unknown origin (FUO) (discussed in Chapter 23) 448

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Acquired immunodeficiency syndrome (AIDS) Vasculitis Inflammatory bowel disease (IBD) Thyroiditis Chronic granulomatous disease (CGD)

Osteomyelitis Although there is limited literature about FDG-PET imaging of osteomyelitis specifically in the pediatric population, FDG-PET has been shown to have a promising role for imaging bone infection in the general population (1–5). This is due to the high metabolic state and increase glucose accumulation by the inflammatory cells (6). Unlike in adults, osteomyelitis in children usually results from hematogenous spread of microorganisms to bones. Infection usually affects a single bone and typically involves the metaphysis of long bone, most commonly the tibia, femur, or humerus. The clinical presentation of osteomyelitis includes local pain and swelling, fever, chills, and malaise. The most common infecting organisms are streptococci and Staphylococcus aureus in neonates, and S. aureus in the pediatric population. The diagnosis can usually be established with positive triple-phase bone scintigraphy and blood culture. Although bone scintigraphy is highly sensitive and specific for the diagnosis of osteomyelitis in intact bone, interpretation is complicated in the presence of a coexisting fracture and surgical intervention at the site of suspected osteomyelitis. In this latter setting, further imaging using an infection radiotracer such as 67Ga, 111In-labeled leukocytes, and 18 F-FDG is often necessary to increase the specificity for osteomyelitis. The most specific method is with 111In-labeled leukocytes; however, this is sensitive only for acute infection. 67Ga is preferred to 111In-labeled leukocytes for the detection of chronic infection (7,8). Fluorodeoxyglucose-PET also shows promise for the evaluation of chronic osteomyelitis. Unlike other nuclear medicine imaging modalities, FDGPET provides good spatial resolution and intrinsic tomographic images, which allow differentiation of soft tissue infection from osteomyelitis. It also provides results within 3 hours after FDG injection, which is shorter than the few days required with 67Ga imaging. It is also known that hypermetabolism seen on FDG-PET at the site of fractures normalizes relatively rapidly. A fracture may be associated with increased FDG uptake for up to 3 months (9). For this reason, FDG-PET facilitates differentiation of a noncomplicated fracture of greater than 3 months from a pathologic fracture (i.e., infection), and thus is not useful before 3 months. A negative FDG-PET study essentially rules out osteomyelitis (5). Fluorodeoxyglucose-PET also has promise for the monitoring the response to antimicrobial therapy (3). In summary, FDG-PET is a functional imaging modality with high sensitivity for diagnosis of acute and chronic osteomyelitis. The value of PET is limited for the evaluation of acute uncomplicated osteomyelitis. However, in the minority of the cases of osteomyelitis

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involving nonintact bone, FDG-PET has great promise for diagnosis and for monitoring the response to antimicrobial therapy. Acquired Immunodeficiency Syndrome Acquired immunodeficiency syndrome (AIDS) is an infectious disease caused by human immunodeficiency virus (HIV). Morbidity and mortality from HIV infection most commonly occur not from the HIV infection itself but from the malignancies and opportunistic pathogens associated with AIDS. O’Doherty et al. (10) studied the role of PET scanning in patients infected with HIV. Fluorodeoxyglucose-PET scan had a sensitivity and specificity of 92% and 94%, respectively, for the localization of focal pathology requiring treatment. The positive predictive value was greater than for hypermetabolic foci on FDG-PET with intensity greater than that of the liver. Fluorodeoxyglucose-PET can help localize a wide variety of infections such as Cryptococcus neoformans, Pneumocystis carinii pneumonia, Pseudomonas aeruginosa, Mycobacterium tuberculosis, and Mycobacterium avium intracellulare (Fig. 24.1). Furthermore, imaging with FDG using a dual-head coincidence imaging system was shown to provide a higher sensitivity than with 67Ga imaging for the demonstration of a focus of infection in patients with AIDS (11). Positron emission tomography has played a major role in the management of AIDS with central nervous system (CNS) lesions. Patients with HIV who present with a change in mental status or abnormal neurologic signs often have CNS lesions demonstrated on a CT scan or MRI. Toxoplasmosis is the most common infectious etiology of focal CNS lesions, and malignant lymphoma is the most common CNS malignancy in HIV-infected patients. Thallium-201 (201Tl) and 99mTcsestamibi have been used for the differentiation of toxoplasmosis and lymphoma in HIV-infected patients presenting with intracranial mass lesions. Heald et al. (12) reported that FDG-PET has a high accuracy

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Figure 24.1. Fluorodeoxyglucose (FDG)-PET attenuation corrected imaging demonstrates diffuse and bilateral increased FDG uptake in the lungs. Maximal intensity projection (A), transaxial (B), sagittal (C), and coronal (D) are shown. The final diagnosis was Pneumocystis carinii pneumonia established by bronchoalveolar lavage.

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Figure 24.2. Biopsy-proven central nervous system (CNS) lymphoma involving the left parietal lobe shown on FDG-PET maximal intensity projection images in the anterior (A), right lateral (B), posterior (C) and left lateral (D) projections.

for the differentiation of CNS lymphoma from infections in the setting of brain mass lesions (Fig. 24.2). Lymphoma is associated with intense hypermetabolism as compared to infections. In that study, there were two false-positive cases due to progressive multifocal leukoencephalopathy demonstrating intense hypermetabolism on FDG-PET. Studies are currently under way to assess the accuracy of FDG-PET for the characterization of brain lesion in patients with AIDS (Fig. 24.2). Fluorodeoxyglucose-PET has great promise to become a standard modality for localization, for the determination of the extent of opportunistic infections, and for the differentiation of CNS lymphoma from opportunistic infection in patients with brain mass lesions associated with AIDS. Vasculitis Vasculitis is defined as an inflammatory process associated with accumulation of leukocytes in the blood vessel wall and reactive damage to the mural structures. It is typically classified by the size of vessels most commonly involved by the disease. In several studies, FDG-PET has been shown to be useful for the evaluation of large vessel vasculitides, such as Takayasu disease and giant cell arteritis in arteries measuring more than 4 mm in diameter (13–21), particularly for the initial diagnosis and for the assessment of response to treatment. In children, Kawasaki disease (KD) and Henoch-Schönlein purpura are the most common vasculitides. Kawasaki disease is a vascular inflammatory disorder of unknown etiology that is usually self-limited.

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The clinical manifestations include fevers, erythema, edema, mucositis, lymphadenopathy, and conjunctivitis. Diagnosis is usually established by history and physical examination. The most serious complication is myocardial infarction, for which echocardiogram is used for the evaluation of KD. Fluorodeoxyglucose-PET has been shown to be helpful for the evaluation for myocardial viability in patients with KD and previous myocardial infarct (22). HenochSchönlein purpura is a small vessel inflammatory disease to the skin, kidneys, gastrointestinal tract, lungs, and CNS. Because the small vessels are the predominant sites of involvement, FDG-PET is not expected to be a sensitive modality for the diagnosis of HenochSchönlein purpura. In the adolescence population, Takayasu arteritis (TA) is the most common cause of vasculitis. It is a large vessel granulomatous inflammatory process affecting the aorta and its major branches. The signs and symptoms are nonspecific, such as fevers, weight loss, and lethargy. Because of the nonspecificity of these symptoms, TA may be undiagnosed for several months to years. Complications include aortic aneurysms, rupture, stenosis and thrombus, congestive heart failure, ischemic strokes, and end-organ infarcts. The diagnosis of TA is established by invasive angiography or MR angiography. However, diagnosis is difficult because the structural changes seen by contrast angiography are only seen late during the disease. Magnetic resonance angiography is currently becoming the modality of choice for diagnosis early in the disease. It would demonstrate the inflammatory wall thickening of the involved vessel in the early phases of the disease. Positron emission tomography with FDG also has promise in the evaluation of patients with TA. Hara et al. (23) reported a case of early TA in which the involved vessels demonstrated increased FDG uptake on PET imaging. Meller et al. (24) have shown subsequently in a study of five patients that FDG-PET is a suitable modality for the diagnosis of early TA (Fig. 24.3). In another study that included 15 patients, one with TA, FDG-PET detected more vascular areas involved by the inflammatory process than did the MRI (25). Fluorodeoxyglucose-PET has also been shown to be a promising modality for the early evaluation of the response to treatment of vasculitis (15,17) as the FDG-PET scan normalizes following successful treatment. Fluorodeoxyglucose-PET shows the potential to have an important role in the early diagnosis and monitoring treatment of patients with large and medium vessel vasculitis (Fig. 24.3). Inflammatory Bowel Disease Inflammatory bowel disease (IBD) is an inflammatory disease that affects the gastrointestinal tract. The etiology is uncertain but is probably immune-mediated. There are two main categories of IBD: Crohn’s disease and ulcerative colitis. Crohn’s disease can involve any region along the gastrointestinal tract from the mouth to the anus, and typically presents with diarrhea, abdominal pain, and weight loss. Ulcerative colitis involves the rectum and extends proximally, is limited to the

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Figure 24.3. Initial FDG-PET images in the coronal and sagittal planes demonstrating intense FDG activity in the thoracic aorta (large arrows). Follow-up study demonstrated normalization in the ascending aorta (small arrow) and partial resolution in the descending aorta (medium arrow). [Source: Meller et al. (25), with permission of Springer.]

large intestine, and typically presents with bloody diarrhea, abdominal pain, and tenesmus. There are several extraintestinal manifestations of IBD, which include ocular manifestations, nephrolithiasis, arthropathy most commonly affecting large joints, primary sclerosing cholangitis, and erythema nodosum. Positron emission tomography is a noninvasive modality that was reported to be helpful for the detection of disease activity in patients

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with IBD (26). However, the presence of physiologic FDG activity in the large intestine can affect the sensitivity and specificity of PET for the evaluation of IBD. Despite this limitation of FDG-PET, Neurath et al. (27) reported a sensitivity of 85% with FDG-PET for the demonstration of disease activity in Crohn’s disease, which was significantly superior to that of other noninvasive imaging methods including MRI and leukocyte scintigraphy, and a specificity of greater than 89%. Recently, investigators demonstrated clinically feasible methods of labeling FDG with leukocytes (28). The PET images with FDG-labeled leukocytes demonstrate minimal tracer activity in the healthy gastrointestinal and urinary tract as compared to FDG-PET images. Therefore, PET with FDG-labeled leukocytes provides abdominopelvic images with minimal hindrance from physiologic distribution of the radiotracer. The intensity of foci of FDG-labeled leukocytes activity correlated well with the degree of inflammation on histology (28). In brief, FDG-PET is a noninvasive modality that has shown great promise for the detection of inflamed segments in patients with IBD. Studies are currently under way to assess the accuracy of FDG-labeled leukocytes, which will provide abdominopelvic images that are not hindered by normal physiologic activity in the gastrointestinal and urinary tract. Thyroiditis Thyroiditis is defined as an inflammatory process involving the thyroid. Although it is most prevalent between the third and fifth decades of life, it has been reported at all ages. Several types of thyroiditis exist, most commonly chronic lymphocytic (Hashimoto’s) thyroiditis, subacute thyroiditis, and silent thyroiditis. Thyroiditis can present incidentally as diffuse hypermetabolism involving the thyroid gland on FDG-PET (29–31). The differential diagnosis for diffuse hypermetabolism in the thyroid glands includes Graves’ disease (32) and subclinical hypothyroidism associated with elevated serum thyroid-stimulating hormone (TSH) without any other thyroid pathology (33). Thyroiditis can be distinguished from thyroid cancer, which usually demonstrates focal hypermetabolism in the nodule. In summary, the presence of diffuse hypermetabolism of the thyroid should raise the suspicion of subclinical hypothyroidism or thyroiditis in patients without symptoms of hyperthyroidism. Chronic Granulomatous Disease Chronic granulomatous disease (CGD) is a rare primary immunodeficiency disorder that results in recurrent, often life-threatening, bacterial and fungal infections. The vast majority of patients first presents during infancy or childhood. Chronic granulomatous disease is suspected to result from the inability of the phagocytes to produce adequate quantities of superoxide radicals to kill catalase positive bacteria and fungi. The diagnosis is established by determining the phagocytic cells’ oxidase activity. Treatments for patients with CGD include

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aggressive treatment of infection, lifelong antibiotic prophylaxis, and g-interferon therapy. This disease can be cured by bone marrow transplantation, provided that the patient does not have any underlying infection at the time of transplant (34). Computed tomography scan has a valuable role in localizing the sites and extent of infectious foci in CGD patients. However, it cannot differentiate active lesions from chronic inactive lesions. Fluorodeoxyglucose-PET is a suitable imaging modality that can differentiate active infectious lesions from chronic inactive lesions by the presence of increased FDG accumulation in inflammatory tissues (6,26). In a study involving seven children with CGD, FDG-PET was compared with CT scan for the accuracy of the detection of infective foci (35). The number of lesions detected by FDG-PET and CT scan was 116 and 126, respectively. Fifty-nine lesions suspicious for active infection on CT scan were excluded by PET, and an additional 49 infectious lesions not seen on CT were detected by PET. The infectious agents were identified in all seven patients based on the FDG-PET results. Early identification of active lesions and differentiation of active lesions from chronic inactive lesions with therapy are important to prevent drug-related toxicities from ineffective or inappropriately prolonged treatment (Fig. 24.4). In summary, FDG-PET is useful for the management of patient with CGD. It provides the ability to differentiate active infection from chronic inactive granuloma. A positive PET scan indicates that infection is present and that the abnormal hypermetabolic focus can be biopsied. A negative PET scan indicates that there is no evidence of infection. This would justify the discontinuation of aggressive,

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Figure 24.4. Corresponding transaxial images of FDG-PET (A,C) and CT scan (B,D) showing inactive lesion (A,B) and active lesions (C,D) due to Actinomyces naeslundii. [Source: Gungor et al. (35), with permission from the BMJ Publishing Group.]

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potentially toxic antimicrobial treatment and qualify the patient to be a candidate for bone marrow transplantation.

Differentiation of Infectious or Inflammatory Processes from Malignancy 18

F-fluoro-2-deoxyglucose is a glucose analogue. Its accumulation is not specific to tumors. It has been demonstrated that tumors as well as inflammatory and infectious processes frequently accumulate FDG (5,36), which may result in false-positive interpretation of FDG-PET for the presence of tumors. Tumors typically exhibit more intense FDG activity than inflammatory and infectious lesions. The standard uptake value (SUV) is a semiquantitative measurement of the intensity of uptake (see below). However, there is considerable overlap of the SUV of benign and malignant lesions. This makes the differentiation of benign from malignant lesions difficult if only one time point is used for imaging, particularly for lesions with mild to moderate FDG intensities (SUVs ranging from 1 to 5). The SUV can be calculated as follows: SUV =

Activity in MBq mL ¥ (Decay factor of 18 F after injection) Injected dose in MBq ¥ Body weight in g

-1

It has been demonstrated that the intensity of FDG accumulation in inflammatory tissues is maximal at approximately 60 minutes after injection and gradually decreases afterward (37). Lodge et al. (38) subsequently reported significantly different time-activity responses of benign and malignant lesions. Benign lesion peak FDG activity occurred within 30 minutes, whereas malignant lesions’ maximal activity occurred at approximately 4 hours after injection. The different FDG uptake patterns may be attributed to the different enzymatic expression of hexokinase and glucose-6-phosphatase in benign and in malignant lesions. Tumors typically exhibit decreased glucose-6phosphatase activity as compared to benign lesions (39,40). As a result, the hexokinase/glucose-6-phosphatase ratio is increased in tumors, which may explain why tumors demonstrate increasing FDG accumulation over a longer period of time after injection. Unlike tumors, mononuclear cells, which predominate in chronic inflammatory processes, have increased glucose-6-phosphatase activity (41). This may account for the shorter time to peak FDG accumulation after injection as compared with tumors. For this reason, dual-time point imaging is sometimes helpful for the differentiation of benign from malignant lesions. Dual-time point imaging with FDG-PET is a technique that has been found to be helpful for distinguishing tumors from benign lesions in various conditions (42–45). In this technique, the first scan is performed using the same method as in single-time point imaging. The second scan is performed in the site of the lesion in question. Factors affecting the accuracy of this technique are the time of the first scan after injection and the time interval between the first and second scans. Because

M.P. Hickeson 12 time 2 time 1

8

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time 2 4 Benign (Inflammation) Malignancy 0 0

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Figure 24.5. Plot of standard uptake value (SUV) versus time after FDG injection for inflammatory and malignant lesions.

FDG uptake by inflammatory cells peaks in intensity at about 60 minutes after injection, the suggested time of the first scan should be at least 60 minutes after FDG administration. The time interval between the first and second scans should be at least 30 minutes to provide adequate additional accumulation of FDG in tumors and differentiation between benign lesions and tumors (Fig. 24.5) (45). The positive interpretation criterion of this technique is an increase in SUV by at least 10% between the first to second scans (43). Dual-time point imaging is a helpful technique for differentiating benign from malignant lesions, particularly for those with mild or moderate FDG accumulation. Malignant lesions increase in intensity on delayed imaging, and benign lesions demonstrate stable or decreasing intensity on delayed imaging.

Conclusion Positron emission tomography is a noninvasive modality that shows great promise for the evaluation of patients with infections. The most commonly used radiopharmaceutical is FDG. With the availability of further studies, infection and inflammation may become a major clinical indication for FDG-PET in the clinical practice of medicine.

References 1. Robiller FC, Stumpe KD, Kossmann T, Weisshaupt D, Bruder E, von Schulthess GK. Chronic osteomyelitis of the femur: value of PET imaging. Eur Radiol 2000;10(5):855–858. 2. De Winter F, Vogelaers D, Gemmel F, Dierckx RA. Promising role of 18-Ffluoro-D-deoxyglucose positron emission tomography in clinical infectious diseases. Eur J Clin Microbiol Infect Dis 2002;21(4):247–257.

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25 Inflammatory Bowel Disease Jean-Louis Alberini and Martin Charron

In the 1970s, research with positron emission tomography (PET) expanded in the fields of cardiology and neurology, but since the 1990s a dramatic upsurge of PET occurred in oncology applications using mostly fluorodeoxyglucose (FDG). This development can be explained by the ability to obtain whole-body acquisition and good image quality and by an improvement of the availability of FDG. However, FDG is not tumor specific. False-positive FDG-PET results in cases of infection and inflammation are well known (1,2). The first report of PET use in infection was the description of FDG uptake in abdominal abscesses in 1989 (3). This led some to consider PET with FDG as a useful tool for rapid detection of infectious processes (4). This property was considered as an opportunity to use FDG-PET in the diagnosis and followup of infectious or inflammatory processes, where it can replace other investigations, for instance, using white blood cell scintigraphy as well as Ga-67. Another potential source of nonmalignant increased FDG uptake is the presence of physiologic activity (in brown fat tissue, muscles, glands, lymphoid tissue). Development of PET–computed tomography (CT) scanners in 2001 allowed decreased acquisition time and improved image analysis by limiting false-positive results due to these physiologic activities. Localization of increased FDG uptake is improved when PET and CT images are co-registered, and PET and CT interpretations can be improved when they are associated.

Physiologic FDG Colonic Activity Although the FDG uptake pattern in the normal colon and intestine is usually mild to moderate, there can be instances of more intense uptake. Segmental and intense colonic increased uptake can be related to inflammation, but uptake in the cecum and descending colon is common in patients without inflammatory bowel disease with a rate estimated to be 11% in a series of 1068 patients (5). The presence of irregular or focal intense accumulation was reported in asymptomatic 461

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patients (6). Different kind of colitis associated with FDG increased uptake have been reported (7–9). Causes of uptake are not clear, but several hypotheses have been suggested (10–12). It could be caused by any of the following: • Smooth muscle activity in relation with peristaltism (6,10–12) • Accumulation of FDG in superficial mucosal cells and a possible shedding of FDG in the stool (13) • Intraluminal leak of FDG through tight junctions between epithelial cells related to an increased permeability (6) or maybe related to the presence of WBC (13) • Presence of lymphoid tissue (14) • Bacterial uptake (15) The published data for the increased uptake associated with peristaltism are contradictory. The use of drugs with antiperistaltic effects (atropine, sincalide) has not shown any difference of the level of intestinal FDG uptake with the baseline state in five young volunteers (16). In another study (17), the use of N-butylscopolamine enabled bowel FDG uptake to decrease. A higher incidence of colonic uptake, especially in the descending colon, was associated with constipation (6). This increased uptake can be explained by a stercoral stasis, which may be responsible for stool accumulation and for an increase of peristaltic motion. Presence of FDG was noted in stools (6). This has led to the proposal of an intestinal preparation with iso-osmotic solution (13). Another hypothesis to explain increased colic uptake was the presence of lymphoid tissue in the cecum walls (14) because it is known that FDG can accumulate in other sites of lymphoid tissue as well as tonsils and adenoids in the Waldeyer ring (18). Finally, it is difficult to determine the mechanism originally responsible for increased uptake.

PET Imaging Compared to Other Nuclear Imaging Techniques Endoscopic and radiologic methods of disease localization are more invasive when compared with the technetium-99m (99mTc)–white blood cell (WBC) scan and tend to produce more discomfort as a result of the instrumentation and preparation for the procedure (e.g., bowel cleansing). Moreover, several studies are needed to analyze the entire bowel, because colonoscopy cannot evaluate the entire small bowel. There is a need for a noninvasive technique that can be utilized in the followup of pediatric patients. The 99mTc-WBC scan seems ideally suited to obtain a precise temporal snapshot of the distribution and intensity of inflammation, whereas radiographic modalities of investigation tend to represent more chronic changes. An additional advantage is high patient acceptability, especially in children. Patients prefer the 99mTcWBC scintigraphy to barium study or enteroclysis. The effective dose equivalent for a 99mTc-WBC study is approximately 3 mSv, whereas it is on the order of 6 mSv for a barium small bowel follow-through or 8.5 mSv for a barium enema. A high yield (percent of positive studies)

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is noted at 30 minutes (88%). The test and acquisition can be terminated if there is a clinical need to shorten the examination time. Scintigraphy with 99mTc-WBC has been reported to be sensitive for the detection of inflammation in adults. The correlation between scintigraphic and endoscopic findings is close enough that scintigraphy can supplement left-sided colonoscopy in the event that total colonoscopy is technically impossible in a selected case. It appears likely that the 99m Tc-WBC scan can be used as a monitoring tool for inflammatory activity in place of colonoscopy. Scintigraphy can also be used to document the proximal extension of ulcerative proctosigmoiditis or postoperative recurrence of Crohn’s disease (CD). The 99mTc-WBC scan is occasionally useful to assess the inflammatory component of a stricture seen on a small bowel follow-through. However, 99mTc-WBC scintigraphy has limitations. It is not useful in defining anatomic details such as strictures, prestenotic dilations, or fistulas, which are best evaluated by barium radiographic studies. Occasionally, in a patient with CD, it can be difficult to distinguish the large bowel from small bowel if the uptake is focal, because landmarks disappear. The presence of gastrointestinal (GI) bleeding occurring at the same time as the 99mTc-WBC study can complicate the interpretation of findings. The value of WBC scintigraphy is well established in the diagnosis of inflammatory bowel disease in children (19–22). Theoretically, FDGPET offers some advantages compared to other radionuclide imaging methods. First, it allows noninvasive study of children and avoids some drawbacks inherent in WBC scintigraphy performed with indium 111 (111In) or 99mTc-labeled leukocytes or granulocytes (23). Second, WBC scintigraphy is a time-consuming technique due to the delay for labeling (approximately 2 hours) and the required interval between injection and image acquisition. Delayed images performed approximately 4 hours after injection or later are recommended and probably essential (24). This delay should be compared to the 2- to 3-hour delay required for an FDG-PET scan. Third, WBC scintigraphy exposes the patient to the risk of contamination by infectious agents from the manipulation of blood samples for the labeling and may require a certain amount of blood sample in younger children. The biodistribution of activities in the liver, the urinary tract, and the bone marrow may generate difficulties for the analysis. On the other hand, radiation protection is always a concern in pediatrics; the dose delivered is more favorable with WBC scintigraphy than with FDG-PET (3 mSv vs. 6 mSv) (23). However, WBC scintigraphy was shown to be sensitive and able to provide semiquantitative data on the severity and the extent of involved segments by inflammation (19–23,25) with a good correlation with endoscopic findings and clinical index. It was shown that WBC scintigraphy helps to differentiate continuous and discontinuous colitis (between Crohn’s disease and ulcerative colitis) (26). Lack of anatomic information is no longer a limitation for this technique because of the introduction of combined single photon emission computed tomography (SPECT) and CT systems, but the role of the co-registration in

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this situation is not yet validated. However, this technique increases the dose delivered to the patient. In published studies using WBC scintigraphy, imaging was performed classically with static views (19–23,25), but it was shown that SPECT can improve the quantification (25). However, g-emitter imaging lacks spatial resolution, and its assessment of the intensity of the bowel activity is only semiquantitative. The main advantage of PET imaging in this field is the opportunity to obtain three-dimensional (3D) slices in one procedure in a shorter time than SPECT takes and with a better image quality. Furthermore, PET imaging allows a more accurate semiquantitative analysis using standard uptake values (SUVs). In the first two published studies (27,28), the method for the semiquantitative analysis of FDG uptake was a measure of a ratio of maximum uptake between intestine and vertebral body. Now most of the PET scans are performed with correction attenuation using external g-emitters sources or CT; SUV data are easily available. Currently no data show that the use of PETCT for this indication can improve the performance of PET by the association of anatomic and metabolic data. The role of PET in inflammatory bowel disease is not clearly established even if some publications have shown promising results with FDG. However, the presence of physiologic colonic activity is a challenge in this situation and leads to the conclusion that FDG is probably not the best-suited tracer in inflammatory bowel disease. It is not yet shown that FDG-PET is superior to WBC scintigraphy. New tracers are under investigation or will be developed in order to investigate inflammation more specifically. The role of PET imaging in the evaluation of treatment efficacy has not been yet evaluated. The first studies suggesting that FDG-PET may be a useful tool to identify active inflammation in inflammatory bowel disease in adults and in children were published in Lancet (27,28). In the first study, FDGPET was used to assess the treatment efficacy on a long-term followup in six patients. A correlation between PET and endoscopic findings was found in five patients with true-positive PET results; PET and endoscopy were negative in one patient. In the second study, performed in a pediatric population affected by inflammatory bowel disease in 18 cases and presenting nonspecific abdominal symptoms in seven cases, sensitivity and specificity were 81% and 85%, respectively, on a per-patient analysis and 71% and 81%, respectively, on a persegment analysis. More recently, performances of FDG-PET were compared to those of hydro–magnetic resonance imaging (MRI) and antigen-95 granulocyte antibodies in a prospective study including 91 patients (29). In this population, 59 patients had Crohn’s disease and 32 patients served as controls (12 irritable bowel syndrome and 20 tumor patients). Positron emission tomography sensitivity was higher than that of MRI or granulocyte antibodies (85.5%, 40.9%, and 66.7%, respectively), but specificity was lower (89%, 93%, and 100%, respectively). Positron emission tomography showed more findings correlated with histopathologic findings than hydro-MRI or granulocyte antibodies. Intensity of FDG uptake used in this study was estimated

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by the measures of SUVmax. No correlation was found among SUVmax, Crohn’s Disease Activity Index, C-reactive protein, and the number of involved segments. N-butylscopolamine was used in this study in order to decrease motion artifacts. This can explain why no intestinal increased FDG uptake was found in the control group of patients with irritable bowel syndrome. The most exciting application of PET imaging is the opportunity to use FDG-labeled leukocytes for this indication, as developed by Forstrom and colleagues (30). The labeling procedure resulted in a satisfactory yield (80%) after a leukocyte incubation with FDG for 10 to 20 minutes in a heparin-saline solution at 37°C. The activity was found more in the granulocyte (78.5% ± 1.4%) than in the lymphocyte-platelet fraction (12.6% ± 1.9%) or in the plasma (5.8% ± 1.8%). The cells’ viability and the stability of labeling were excellent (30). Fluorodeoxyglucose-labeled autologous leukocyte scintigraphy performed in four normal volunteers has shown a predominant uptake in the reticuloendothelial system similar to that of other radiolabeled leukocytes and no gastrointestinal uptake (31). Injection of FDG-labeled leukocytes using 250 MBq (225–315 MBq) exposes to a dose of 3 to 4 mGy approximately, similar to the dose delivered by 111In-labeled WBC scintigraphy. Pio and colleagues (32) have shown that PET imaging using FDG-labeled WBC was feasible and facilitated assessment of bowel inflammation accurately and rapidly in murine and human subjects. In animal models, inflammatory bowel disease was present in Gi2adeficient mice (lacking the signal transducing G-protein) or induced by an injection of exogenous leukocytes. A correlation between intestinal segments with increased uptake of FDG-labeled WBC and histopathologic and colonoscopic findings was found. Their intensity was correlated with the degree of inflammation measured on the pathologic analysis performed on necropsied mice and used as the gold standard. The acquisition protocol used in this study seems very simple because acquisition was started 40 minutes after injection and lasted 30 minutes.

PET and Cancers in Patients with Inflammatory Bowel Disease Patients with inflammatory bowel disease are exposed to a higher risk of colorectal cancer than the general population; for patients with ulcerative colitis this risk can reach a factor of 2. Colorectal cancer is overall observed in 5.5% to 13.5% of patients with ulcerative colitis and in 0.4% to 0.8% in patients with Crohn’s disease (33). Colorectal cancer can account for approximately 15% of all deaths in these patients (34,35). However, the increased risk of colorectal cancer is not well known (34), especially in Crohn’s disease patients (36). Established risk factors include long duration (34), large extent and severity of the disease (37), early disease onset, presence of complicating primary sclerosing cholangitis or stenotic disease, (33) and perhaps a family history of colorectal cancer (38).

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Although this risk does not usually involve children during their childhood because colorectal cancer occurs after several years of the disease onset, it was shown in a meta-analysis (34) that the cumulative probabilities of any child developing cancer were estimated to be 5.5% at 10 years of duration, 10.8% at 20 years, and 15.7% at 30 years. The average age of onset of ulcerative colitis was 10 years in several studies. All these data mean that this child population will require permanent surveillance for early detection of colorectal cancer. The current surveillance strategy includes colonoscopic examinations (39), but its impact on survival in patients with extensive disease is still under debate (40). It seems in different studies that dying by colorectal cancer in the group of patients with colonoscopic surveillance was lower than in the no-surveillance group (40). It is logical to consider that surveillance will facilitate detection of advanced adenomas, adenomas with appreciable villous tissue or high-grade dysplasia, or cancer at an early stage. The optimal interval between surveillance procedures is not established, but a delay of approximately 3 years seems to be cost-effective (41). Because the estimated incidence of colorectal cancer in ulcerative colitis patients can reach 27% over a 30-year period, prevention can lead to the proposal of a prophylactic colectomy. This attitude is questionable considering the complications risk and the consequences on the quality of life (41), but the cumulative colectomy rate can be high after a long duration of disease (42). It was proposed to start this surveillance 7 or 8 years after the disease onset in case of total colitis (33) or immediately in patients with primary sclerosing cholangitis (38). Finally, because of the better acceptance of noninvasive techniques by patients, FDG-PET has a role to play in the surveillance workup in children (when the disease onset is early) or in young adults. Indeed it was shown that FDG-PET is a sensitive tool to detect premalignant colonic lesions (43–46). The presence of colonic nodular-focal FDG findings detected by FDG-PET is suggestive of a premalignant lesion. In a series of 20 patients with nodular colonic FDG uptake on a routine PET-CT scan, we found that these foci were associated with colonoscopic lesions in 75% of the patients (15/20 patients) and in 67% of the total amount of FDG findings (14/21 areas) (47). Histopathologic findings revealed advanced neoplasms in 13 patients (13 villous adenomas and three carcinomas) and two cases of hyperplastic polyps. Co-registration of PET and CT data improved the analysis of colonic FDG uptake by avoiding confusion between abnormal focal uptake and physiologic activity, especially in case of fecal stasis. These results were in agreement with a recent paper (48) in which the authors found nine colorectal carcinomas and 27 adenomas. Among these adenomas, seven were high-grade dysplasia adenomas. Inflammatory lesions were reported in 12 of 69 patients (17%), and the diagnostic was confirmed by endoscopy. There were four cases of diffuse colonic uptake related to three active colitis and one reactivation of ulcerative colitis, and eight cases of segmental colonic uptake with one identified pseudomembranous colitis. This may suggest that PET or PET-CT can play a role in the diagnostic procedure in the

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surveillance strategy of patients with inflammatory bowel disease in order to detect early lesions susceptible to easy removal, that is, neoplasia at a surgically curative stage or, better yet, at a dysplastic, still noninvasive stage. Another situation that exposes inflammatory bowel disease patients to a higher risk of malignant lesion is the presence of primary sclerosing cholangitis. Because of its poor prognosis when diagnosed at an advanced stage (49), early detection of cholangiocarcinoma lesions is crucial. Surgical resection and liver transplantation are the only curative treatments. A study has shown that FDG-PET has the potential to detect small cholangiocarcinoma tumors in nine patients with primary sclerosing cholangitis (50) in spite of its limited spatial resolution. A more recent study (51) in 50 patients with biliary tract cancers of whom 36 had cholangiocarcinoma was not so optimistic on the value of PET in diagnosis of cholangiocarcinoma; PET sensitivity was much higher in the nodular rather than the infiltrating form (85% vs. 18%), and there was a false-positive result in a patient with primary sclerosing cholangitis associated with an acute cholangitis. Its sensitivity to identifying carcinomatosis was very poor, with three false-negative results out of three patients. However, detection of unsuspected distant metastases led to a change in surgical management in 31% (11/36). The FDG-PET performances to detect carcinomatosis or pulmonary metastases were really better in other series (52,53). To conclude, FDG-PET is a useful tool in the diagnosis of cholangiocarcinoma especially for the nodular form, but it can fail to differentiate cholangiocarcinoma from cholangitis. Its value in the preoperative workup to confirm that cholangiocarcinoma lesions are only localized in the liver seems limited, but further studies are required.

Conclusions The main advantages of nuclear medicine methods are their capability to explore metabolic processes at a molecular level, with a quantitative approach, and the potential to label molecules and antibodies that can be proposed as treatments. Ultrasonography, CT, and MRI are suited for the diagnosis of inflammatory bowel disease complications, but the latest technologic improvements have allowed exploration of the intestinal wall with nonirradiating techniques. Although 111In- or 99mTclabeled WBC scintigraphy remains a reliable method for diagnosis of inflammatory bowel disease, it cannot replace colonoscopy. Positron emission tomography as a new nuclear imaging modality offers significant advantages in the diagnosis and follow-up in inflammatory bowel disease because of its better spatial resolution, its volumetric acquisition in one step, the high signal-to-background ratio, the opportunity to quantify signal intensity, its good availability, and the lack of side effects. Although some studies have shown good performance with FDG, it does not seem to be the best suited tracer because of the physiologic colonic uptake. One challenge for FDG-PET imaging in inflammatory bowel disease is to determine if it can be included in the

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surveillance of patients with ulcerative colitis because of a higher risk of colorectal cancer and cholangiocarcinoma in this population. Several studies have shown that FDG-PET is a sensitive and noninvasive method to detect premalignant colonic lesions, especially high-grade dysplasia adenomas. Its place beside the repeated colonoscopic investigations has to be evaluated. Development of new tracers in order to study different metabolisms, inflammatory reactions, and probably immunologic reactions involved in inflammatory bowel disease will be a challenge. The opportunity to label new drugs with positron emitters should be investigated in order to propose clinical tools to evaluate therapeutic efficacy. At the moment, the preliminary results obtained with FDG-labeled leukocytes in humans are very promising.

References 1. Zhuang H, Alavi A. 18-fluorodeoxyglucose positron emission tomographic imaging in the detection and monitoring of infection and inflammation. Semin Nucl Med 2002;32(1):47–59. 2. Zhuang H, Yu JQ, Alavi A. Applications of fluorodeoxyglucose-PET imaging in the detection of infection and inflammation and other benign disorders. Radiol Clin North Am 2005;43(1):121–134. 3. Tahara T, Ichiya Y, Kuwabara Y, et al. High [18F]-fluorodeoxyglucose uptake in abdominal abscesses: a PET study. J Comput Assist Tomogr 1989;13(5):829–831. 4. Sugawara Y, Braun DK, Kison PV, Russo JE, Zasadny KR, Wahl RL. Rapid detection of human infections with fluorine-18 fluorodeoxyglucose and positron emission tomography: preliminary results. Eur J Nucl Med 1998;25(9):1238–1243. 5. Yasuda S, Takahashi W, Takagi S, Fujii H, Ide M, Shohtsu A. Factors influencing physiological FDG uptake in the intestine. Tokai J Exp Clin Med 1998;23(5):241–244. 6. Kim S, Chung JK, Kim BT, et al. Relationship between gastrointestinal F18–fluorodeoxyglucose accumulation and gastrointestinal symptoms in whole-body PET. Clin Positron Imaging 1999;2(5):273–279. 7. Meyer MA. Diffusely increased colonic F-18 FDG uptake in acute enterocolitis. Clin Nucl Med 1995;20(5):434–435. 8. Hannah A, Scott AM, Akhurst T, Berlangieri S, Bishop J, McKay WJ. Abnormal colonic accumulation of fluorine-18–FDG in pseudomembranous colitis. J Nucl Med 1996;37(10):1683–1685. 9. Kresnik E, Gallowitsch HJ, Mikosch P, et al. (18)F-FDG positron emission tomography in the early diagnosis of enterocolitis: preliminary results. Eur J Nucl Med Mol Imaging 2002;29(10):1389–1392. 10. Engel H, Steinert H, Buck A, Berthold T, Huch Boni R, von Schulthess G. Whole-body PET: physiological and artifactual fluorodeoxyglucose accumulations. J Nucl Med 1996;37(3):441–446. 11. Strauss LG. Fluorine-18 deoxyglucose and false-positive results: a major problem in the diagnostics of oncological patients. Eur J Nucl Med 1996;23(10):1409–1415. 12. Delbeke D. Oncological applications of FDG PET imaging: brain tumors, colorectal cancer, lymphoma and melanoma. J Nucl Med 1999;40(4): 591–603.

J.-L. Alberini and M. Charron 13. Miraldi F, Vesselle H, Faulhaber PF, Adler LP, Leisure GP. Elimination of artifactual accumulation of FDG in PET imaging of colorectal cancer. Clin Nucl Med 1998;23(1):3–7. 14. Cook GJ, Fogelman I, Maisey MN. Normal physiological and benign pathological variants of 18–fluoro-2–deoxyglucose positron-emission tomography scanning: potential for error in interpretation. Semin Nucl Med 1996;26(4):308–314. 15. Shreve PD, Anzai Y, Wahl RL. Pitfalls in oncologic diagnosis with FDG PET imaging: physiologic and benign variants. Radiographics 1999;19(1):61–77; quiz 150–151. 16. Jadvar H, Schambye RB, Segall GM. Effect of atropine and sincalide on the intestinal uptake of F-18 fluorodeoxyglucose. Clin Nucl Med 1999;24(12): 965–967. 17. Stahl A, Weber WA, Avril N, Schwaiger M. Effect of N-butylscopolamine on intestinal uptake of fluorine-18–fluorodeoxyglucose in PET imaging of the abdomen. Nuklearmedizin 2000;39(8):241–245. 18. Jabour BA, Choi Y, Hoh CK, et al. Extracranial head and neck: PET imaging with 2–[F-18]fluoro-2–deoxy-D-glucose and MR imaging correlation. Radiology 1993;186(1):27–35. 19. Jewell F, Davies A, Sandhu B, Duncan A, Grier D. Technetium-99mHMPAO labelled leucocytes in the detection and monitoring of inflammatory bowel disease in children. Br J Radiol 1996;69:508–514. 20. Jobling J, Lindley K, Yousef Y, Gordon I, Milla P. Investigating inflammatory bowel disease—white cell scanning, radiology, and colonoscopy. Arch Dis Child 1996;74:22–26. 21. Papos M, Varkonyi A, Lang J, et al. HM-PAO-labeled leukocyte scintigraphy in pediatric patients with inflammatory bowel disease. J Pediatr Gastroenterol Nutr 1996;23:547–552. 22. Shah D, Cosgrove M, Rees J, Jenkins H. The technetium white cell scan as an initial imaging investigation for evaluating suspected childhood inflammatory bowel disease. J Pediatr Gastroenterol Nutr 1997;25:524– 528. 23. Alberini J, Badran A, Freneaux E, et al. Technetium-99m HMPAO-labelled leukocyte imaging compared with endoscopy, ultrasonography and contrast radiology in children with inflammatory bowel disease. JPGN 2001; 32:278–286. 24. Charron M, del Rosario F, Kocoshis S. Comparison of the sensitivity of early versus delayed imaging with Tc-99m HMPAO WBC in children with inflammatory bowel disease. Clin Nucl Med 1998;23:649–653. 25. Charron M, del Rosario F, Kocoshis S. Pediatric inflammatory bowel disease: assessment with scintigraphy with 99mTc white blood cells. Radiology 1999;212:507–513. 26. Charron M, del Rosario F, Kocoshis S. Use of technetium-tagged white blood cells in patients with Crohn’s disease and ulcerative colitis: is differential diagnosis possible? Pediatr Radiol 1998;28:871–877. 27. Bicik I, Bauerfeind P, Breitbach T, von Schulthess G, Fried M. Inflammatory bowel disease activity measured by positron-emission tomography. Lancet 1997;350:262. 28. Skehan S, Issenman R, Mernagh J, Nahmias C, Jacobson K. 18Ffluorodeoxyglucose positron tomography in diagnosis of pediatric inflammatory bowel disease. Lancet 1999;354:836–837. 29. Neurath MF, Vehling D, Schunk K, et al. Noninvasive assessment of Crohn’s disease activity: a comparison of 18F-fluorodeoxyglucose positron emission tomography, hydromagnetic resonance imaging, and granulocyte

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26A Hyperinsulinism of Infancy: Noninvasive Differential Diagnosis Maria-João Santiago-Ribeiro, Nathalie Boddaert, Pascale De Lonlay, Claire Nihoul-Fekete, Francis Jaubert, and Francis Brunelle

Hyperinsulinism (HI) is the most important cause of recurrent hypoglycemia in infancy. The hypersecretion of insulin induces profound hypoglycemias that require aggressive treatment to prevent the high risk of neurologic complications (1,2). Hyperinsulinism can be due to two different histopathologic types of lesions, a focal or a diffuse form (3,4), based on different molecular entities despite an indistinguishable clinical pattern (5–9). In focal HI, which represents about 40% of all cases (10), the pathologic pancreatic b cells are gathered in a focal adenoma, usually 2.5 to 7.5 mm in diameter. Conversely, diffuse HI corresponds to an abnormal insulin secretion of the whole pancreas with disseminated b cells showing enlarged abnormal nuclei (11). Finally, about 10% of HI cases are clinically atypical and could not be classified, having unknown molecular basis and histopathologic form (12). The two histopathologic forms correspond to two distinct molecular entities most implicating the SUR1 and KIR6.2 genes. The focal HI is associated with a loss of a maternal allele from chromosome 11p15 in the lesion and a somatic reduction to homozygosity in the paternally inherited mutation in either of the genes encoding the two subunits of the K+ ATP channel: the sulfonylurea receptor type 1 (SUR1, MIM600509) and the inward-rectifying potassium-channel (KIR6.2, MIM600937). The diffuse form of HI is more heterogeneous and its genetic basis has been recognized in only 50% of the cases. Diffuse HI involves the genes SUR1 and KIR6.2 in recessively inherited hyperinsulinism or, more rarely, dominantly inherited hyperinsulinism. The glucokinase gene or other loci are also involved in dominantly inherited hyperinsulinism. The glutamate dehydrogenase gene is concerned when hyperammonemia is associated with hyperinsulinism. Control of HI is attempted through medical treatment with diazoxide, nifedipine, or octreotide (13–15), but pancreatectomy is the only 472

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option for patients resistant to these treatments (10,16). Therefore, the differential diagnosis between the two forms becomes of major importance because their surgical treatment and the outcome differ considerably. Focal HI is totally cured by the selective resection of the adenoma, whereas diffuse forms of HI require a subtotal pancreatectomy with severe iatrogenic diabetes as consequence (17,18). The localization of insulin hypersecretion before surgery is only possible through pancreatic venous catheterization (PVC), allowing a pancreatic map of insulin concentrations, with an eventually additional pancreatic arterial calcium stimulation (PACS) (19–21). Pancreatic venous catheterization is invasive and technically difficult to perform and requires general anesthesia. The concentrations of plasmatic glucose must be maintained between 2 and 3 mmol/L before and during the PVC. Moreover, all medical treatments have to be stopped 5 days before the study. Therefore, it is of major interest to find another less invasive way to differentiate between focal and diffuse HI. This method should precisely localize the pathological area of focal HI to guide the surgeon. L-dihydroxyphenylalanine (L-DOPA) is a precursor of catecholamines that is converted to dopamine by the aromatic amino acid decarboxylase (AADC) enzyme. In addition to its role as a precursor of noradrenaline and adrenaline, dopamine is a transmitter substance in the central and peripheral nervous system. The capacity to take up and decarboxylate amine precursors such as L-DOPA or 5-hydroxytryptophan (5-HTP) and store their amine biogenic (dopamine and serotonin) is characteristic of neuroendocrine cells. Pancreatic cells contain markers usually associated with neuroendocrine cells, such as tyrosine hydroxylase, dopamine, neuronal dopamine transporter, vesicular dopamine transporter, and monoamine oxidases A and B (22–24). Pancreatic islets have been shown to take up L-DOPA and convert it to dopamine through the aromatic amino acid dopa decarboxylase (25–27). The term neuroendocrine tumors comprises a wide variety of rare tumor entities that may originate either from pure endocrine organs (e.g., pituitary adenomas), from pure nerve structures (e.g., neuroblastomas), or from elements of the diffuse (neuro)endocrine system as all endocrine tumors of the gastroenteropancreatic (GEP) tract. These neuroendocrine disordered cells share similar cytochemical and ultrastructural characteristics. They have the capacity to take up and convert dopamine precursors to amines or peptides, or both, which they store in secretory granules in the cytoplasm. Yet, it has been discovered that other cells throughout the body share this ability of amine precursor uptake and decarboxylation (APUD). The term APUD has lately been found to be inadequate, because several cell types included in the system do not metabolize amines. Furthermore, there is evidence that some APUD cell types are not of neural crest origin but are derived from endoderm (28). Positron emission tomography (PET) performed with fluorine-18 (18F)-fluoro-L-dihydroxyphenylalanine (18F-fluoro-L-DOPA) has been extensively used to study the central dopaminergic system. Neverthe-

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less, several recent studies have demonstrated the usefulness of this radiotracer to detect neuroendocrine tumors as pheochromocytomas, thyroid medullar carcinomas, or gastrointestinal carcinoid tumors that usually contain secretory granules and have the ability to produce biogenic amines (29,30).

Technique Data Acquisition and Processing The patients fasted for at least 6 hours prior to the PET study, and their medications were stopped for at least 72 hours. During all PET studies, normoglycemia is maintained by glucose infusion, which is carefully adjusted according to frequent blood glucose monitoring. Maximal glucose infusion rates between 6.4 and 13.2 mg/ kg/min are needed. Positron emission tomography acquisition is performed under light sedation (pentobarbital associated or not with chloral). Patients are placed in the supine position in the tomograph using a three-dimensional (3D) laser alignment. To ensure the optimal position in the scanner and to avoid movement artifacts, children should be comfortably immobilized during the study acquisition by placing them in a vacuum mattress. Intravenous bolus injection of a mean of 4.0 MBq/kg 18F-fluoro-L-DOPA is done 30 to 50 minutes before transmission acquisition. Tissue attenuation is measured postinjection and before emission acquisition. Transmission scans (2D acquisition mode) lasted 2.5 minutes per bed position (field of view of 15 cm), with two or three steps, according to the height of the patient, from the neck to the hip. After segmentation, they are used for subsequent correction of attenuation of emission scans. Thorax-abdomen emission scans (3D acquisition mode) start between 45 to 65 minutes after the radiotracer injection; 2.5-minute step acquisition, two or three steps for one scan, is acquired over 30 minutes. The emission sets are corrected for scatter using a model-based correction, allowing the simulation of the map of single scatter events. The images are reconstructed using an attenuation weighted ordered subset expectation maximization iterative algorithm with four iterations and six subsets. Data Analysis The reconstructed images are evaluated in a 3D display using axial, coronal, and sagittal views to define pancreas, which invariably has a sufficiently high uptake of 18F-fluoro-L-DOPA to distinguish it from the surrounding organs in the upper abdomen. Variable uptake is also seen in the gallbladder, biliary duct, and duodenum; nevertheless all of them could be discerned from pancreatic target tissue uptake.

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For each patient, all thorax-abdomen emission scans are assembled with bed position overlap. A gaussian filter was used to smooth the images. This assembled image could be recalculated to provide the standard uptake value (SUV) where the radioactivity concentration in each pixel is divided by the total injected dose of 18F-fluoro-L-DOPA at the beginning of the emission acquisition and the body weight. However, this imaging sequence is not crucial, and only one thoraxabdomen emission scan can be done 60 minutes postinjection. In fact, pancreas uptake of 18F-fluoro-L-DOPA is constant during the emission acquisition (30 minutes). Eighteen children with HI were studied using PET and 18F-fluoro-LDOPA. Five of them presented an abnormal focal radiotracer uptake whereas a diffuse uptake pattern was observed in the pancreatic area of the other patients. All patients with focal radiotracer uptake were submitted to surgery, and the localization of the focal form characterized by PET was confirmed by histologic samples. Figure 26A.1 illustrates an example of a typical focal form of HI. A diffuse accumulation pattern of 18F-fluoro-L-DOPA was observed in the whole pancreas for patients with diffuse insulin secretion (Fig. 26A.2). Diffuse HI forms resistant to medical treatment (four patients) were operated and PET results were supported by the data from histologic analysis after subtotal pancreatectomy.

Figure 26A.1. Focal hyperinsulinism (HI). The abnormal focal increased uptake of the radiotracer is visualized in the pancreas on coronal and axial projections (arrows). Physiologic distribution of the radiotracer with higher accumulation in the kidneys and the urinary bladder and a lower accumulation in the liver is also observed.

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Figure 26A.2. Diffuse HI. The abnormaldiffuse increased uptake of the radiotracer is visualized in all the pancreas on coronal and axial projections (arrows).

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and in vivo-tumor visualization using positron emission tomography with 11 C-harmine. Nucl Med Biol 2003;30:669–679. Oei HK, Gazdar AF, Minna JD, Weir GC, Baylin SB. Clonal analysis of insulin and somatostatin secretion and L-dopa decarboxylase expression by a rat islet cell tumor. Endocrinology 1983;112:1070–1075. Lindstrom P. Aromatic-L-amino-acid decarboxylase activity in mouse pancreatic islets. Biochim Biophys Acta 1986;884:276–281. Borelli MI, Villar MJ, Orezzoli A, Gagliardino JJ. Presence of DOPA decarboxylase and its localisation in adult rat pancreatic islet cells. Diabetes Metab 1997;23:161–163. Oei HK, De Jong M, Krenning EP. Gastroenteropancreatic neuroendocrine tumors. In: Feinendegen LE, Shreeve WW, Eckelman WC, Bahk YW, Wagner HN, eds. Molecular Nuclear Medicine. Heidelberg: SpringerVerlag, 2003:385–397. Hoegerle S, Altehoefer C, Ghanem N, et al. Whole-body 18F DOPA PET for detection of gastrointestinal carcinoid tumors. Radiology 2001;220:373–380. Hoegerle S, Nitzche E, Altehoefer C, et al. Pheochromocytomas: detection with 18F DOPA whole-body PET-initial results. Radiology 2002;222:507–512.

26B Hyperinsulinism of Infancy: Localization of Focal Forms Olga T. Hardy and Charles A. Stanley

Congenital Hyperinsulinism Congenital hyperinsulinism is the most common cause of persistent hypoglycemia in infants and children (1). Infants with severe forms of the disorder (formerly termed nesidioblastosis) present with hypoglycemia in the newborn period and are at high risk of seizures, permanent brain damage, and retardation. Infants with congenital hyperinsulinism may have either focal or diffuse abnormalities of the pancreatic b cells. In cases with diffuse disease, an underlying defect in the b-cell adenosoine triphosphate (ATP)-dependent potassium channel may be present, caused by recessive loss of function mutations of the two genes encoding the KATP channel, SUR1 or Kir6.2 (1,2). These mutations may also cause focal hyperinsulinism in which there is an area of b-cell adenomatosis due to loss of heterozygosity for the maternal 11p region and expression of a paternally derived KATP channel mutation (3). Most of the cases with severe hyperinsulinism do not respond to medical therapy with diazoxide, octreotide (Fig. 26B.1), or continuous feedings and require near-total pancreatectomy to control hypoglycemia. However, cases of focal hyperinsulinism can be treated effectively with partial pancreatectomy. The surgical approach and therapeutic outcome for the infants depends on preoperatively distinguishing between focal and diffuse forms of hyperinsulinism. This chapter describes the focal lesions of hyperinsulinism, the pancreatectomy procedure, previous methods of determining the site of focal lesions, and the rationale for using positron emission tomography (PET) scans with 18F-fluoro-L-DOPA.

Focal Hyperinsulinism Histologically, focal hyperinsulinism has the appearance of b-cell adenomatosis (Fig. 26B.2) but does not affect pancreatic architecture and is invisible to the naked eye. Focal hyperinsulinism is clonal in origin 479

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Figure 26B.2. Gross and histopathologic section of focal hyperinsulinism. This is an area of focal adenomatosis characterized by a pattern of crowded islets and limited exocrine tissue present in the surrounding periphery. Normal neighboring tissue to the right has an appropriate amount of islets present.

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and the result of a specific loss of maternal alleles (loss of heterozygosity, LOH) in the p15 region of chromosome 11 (4) where the two KATP channel genes, SUR1 and Kir6.2, are located. The maternal LOH results in loss of one or more maternally expressed tumor suppressor genes p57KIP2 and H19 as well as isodisomy for the paternally expressed insulin-like growth factor 2 gene (4). The loss of the maternal 11p thus leads to expansion of a clone of b cells that expresses a paternally derived KATP channel defect. These focal lesions are treatable with focal resection of the affected pancreatic area.

Pancreatectomy Infants with congenital hyperinsulinism that fail medical management require partial or near-total pancreatectomy. During this operation, biopsies from the pancreatic head, body, and tail are examined for b cells with large nuclei and abundant cytoplasm suggestive of diffuse disease. When frozen sections demonstrate the absence of nuclear enlargement in biopsies from the head, body, and tail of the pancreas, further search for a focal lesion is conducted using additional biopsies until the focal lesion is found. Infants in whom frozen sections demonstrate diffuse disease, as evidenced by islet nuclear enlargement in all areas of the pancreas, undergo near-total pancreatectomy, removing approximately 98% of the organ. Many of these children subsequently develop iatrogenic diabetes. Preoperative differentiation between diffuse and focal disease and localization of a potential focal lesion is important to guide the surgical approach and improve surgical outcome.

Localization of Focal Pancreatic Lesions Previous efforts to image focal congenital hyperinsulinism have been unsuccessful, including computed tomography (CT), magnetic resonance imaging (MRI), ultrasonography (preoperative and intraoperative), and radiolabeled octreotide scans (5). As discussed below, pharmacologic tests and techniques using interventional radiology have had limited success. Pharmacologic Tests Children with diffuse hyperinsulinism associated with the two most common mutations of SUR1 display abnormal positive acute insulin responses (AIRs) to calcium and abnormal negative AIR to the KATP channel antagonist tolbutamide as well as an impaired insulin response to glucose (6). It was hypothesized that infants with diffuse and focal diazoxide-unresponsive hyperinsulinism could be distinguished by their AIRs to calcium and tolbutamide stimulation. That is, both types would respond to calcium, but only focal lesions would respond to tolbutamide. This hypothesis was tested in a group of 30 focal and 13 diffuse cases. Only two thirds of these cases responded to calcium;

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although most focal cases responded to tolbutamide, half of the diffuse cases responded as well (7). This probably reflects the fact that some of the disease-causing mutations retain some partial function of the KATP channel (8). As a consequence, preoperative AIR tests cannot be used to distinguish focal vs. diffuse disease. Interventional Radiology Over the past 5 years, we have used the procedure of selective pancreatic arterial calcium stimulation with hepatic vein sampling (ASVS) for localization of focal hyperinsulinism lesions. It relies on the hypothesis that hypersensitivity to calcium stimulation in children with both diffuse and focal hyperinsulinism would make it possible to use selective pancreatic arterial stimulation with hepatic venous insulin sampling to differentiate focal from diffuse disease and to localize focal lesions. The ASVS procedure is carried out under general anesthesia, and plasma glucose levels must be maintained between 60 and 90 mg/dL. A positive response to the ASVS test is defined as a twofold or greater rise in plasma insulin after calcium infusion. A positive response from a single region of the pancreas is taken as evidence of focal disease. Results from a study looking at ASVS in 50 children revealed that ASVS localized the lesion in 24 of 33 focal cases (73%) but correctly diagnosed diffuse disease in only four of 13 cases. The ASVS test has about the same accuracy as transhepatic portal venous insulin sampling (THPVS), which correctly identified the region of focal lesions in only 76% of 45 cases (3). Both of these tests are technically difficult to perform and are associated with significant risks of general anesthesia and intubation, hypoglycemia, femoral artery catheterization and thrombosis, radiation exposure, and need for transfusion due to blood sampling. PET Using 18F-fluoro-L-DOPA for Focal Hyperinsulinism Fluorine-18 (18F)-labeled L-fluoro-DOPA has been used successfully to detect neuroendocrine tumors, such as carcinoids and endocrine pancreatic tumors in adults (9). Neuroendocrine tumors belong to the amine precursor uptake and decarboxylation (APUD) cell system and have the capacity to take up and to decarboxylate amine precursors, transform them into biogenic amines, and store them in vesicles. Thus, these cells can take up radioactively labeled 18F-fluoro-L-DOPA to store as dopamine, which can be detected by PET imaging. 18F-fluoro-LDOPA-PET was not successful in localizing insulinomas but was accurate in localizing focal lesions of hyperinsulinism (10). Researchers in France recently published their experience with 18Ffluoro-L-DOPA PET scan on infants with congenital hyperinsulinism (11). They studied 15 patients with hyperinsulinism based on clinical diagnosis. Under conscious sedation, they injected a mean dose of 4 MBq/kg 18F-labeled L-fluoro-DOPA intravenously 30 to 50 minutes before transmission acquisition. They observed an abnormal focal pancreatic uptake of 18F-fluoro-L-DOPA in five patients and a diffuse uptake in the other 10 patients. All five of the patients with focal uptake

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Figure 26B.3. Focal uptake of 18F-labeled L-fluoro-DOPA believed to be behind the superior mesenteric artery (SMA).

and four of the patients with diffuse uptake underwent surgery. The histopathologic results were consistent with the PET findings in these nine cases. The results from France, as well as preliminary data from a research group in Finland, suggest that 18F-labeled L-fluoro-DOPA is an accurate noninvasive technique to distinguish between focal and diffuse forms of hyperinsulinism and to localize areas of focal lesions. As described in abstracts presented at the Endocrine Society meeting and the International Pediatric Endocrinology conference, our group at the Children’s Hospital of Philadelphia has accumulated preliminary data using 18F-fluoro-L-DOPA-PET in children with congenital hyperinsulinism (Fig. 26B.3). The very encouraging results suggest that this test is 100% accurate in distinguishing diffuse from focal disease and in localizing the site of the focal lesion.

Conclusion Focal hyperinsulinism is an important cause of hypoglycemia in young infants and is potentially curable by surgery. Preliminary information about the success of 18F-fluoro-L-DOPA PET suggests that this may be a method of choice for preoperative identification of focal lesions. An advantage to this technique is that it may be used to select out patients with diffuse disease who may be candidates for nonsurgical treatment. More important, the information acquired using 18F-fluoroL-DOPA-PET should make it possible for the surgeon to cure focal hyperinsulinism by local excision.

Acknowledgment This work was supported in part by National Institutes of Health (NIH) grants RO1 DK 56268 (to C.A.S.) and MO1 RR 00240. O.T.H. was supported by NIH training grant T32 DK63688 (C.A.S.).

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References 1. Stanley CA. Hyperinsulinism in infants and children. Pediatr Clin North Am 1997;44:363. 2. Glaser B, Thornton P, Otonkoski T, Junien C. Genetics of neonatal hyperinsulinism. Arch Dis Child (Fetal Neonatal Ed) 2000;82:F79. 3. de Lonlay-Debeney P, Poggi-Travert F, Fournet JC, et al. Clinical features of 52 neonates with hyperinsulinism. N Engl J Med 1999;340:1169–1175. 4. Verkarre V, Fournet JC, de Lonlay P, et al. Paternal mutation of the sulfonylurea receptor (SUR1) gene and maternal loss of 11p15 imprinted genes lead to persistent hyperinsulinism in focal adenomatous hyperplasia. J Clin Invest 1998;102:1286–1291. 5. Adzick NS, Thornton PS, Stanley CA, Kaye RD, Ruchelli E. A multidisciplinary approach to the focal form of congenital hyperinsulinism leads to successful treatment by partial pancreatectomy. J Pediatr Surg 2004;39: 270–275. 6. Grimberg A, Ferry RJ, Kelly A, et al. Dysregulation of insulin secretion in children with congenital hyperinsulinism due to sulfonylurea receptor mutations. Diabetes 2001;50:322–328. 7. Stanley CA, Thornton PS, Ganguly A, et al. Preoperative evaluation of infants with focal or diffuse congenital hyperinsulinism by intravenous acute insulin response tests and selective pancreatic arterial calcium stimulation. J Clin Endocrinol Metab 2004;89:288–296. 8. Henwood M, Kelly A, MacMullen C, et al. Genotype-phenotype correlations in children with congenital hyperinsulinism due to recessive mutations of the adenosine triphosphate-sensitive potassium channel genes. J Clin Endocrinol Metab 2005;90:789–794. 9. Erikkson B, Bergstrom M, Orlefors H, Sundin A, Oberg K, Langstrom B. PET for clinical diagnosis and research in neuroendocrine tumors. In: Sandler, Coleman, Patton, Wackers, Gottschalk, eds. Diagnostic Nuclear Medicine, 4th ed. Philadelphia: Lippincott Williams & Wilkins, 2003:747– 754. 10. Boddaert N, Riberio MJ, Nuutila P, et al. 18F-fluoro-L-DOPA PET SCAN in focal forms of hyperinsulinism of infancy. Presented at the 40th annual congress of the European Society of Paediatric Radiology, June 2003, Genoa, Italy. 11. Ribeiro M, De Lonlay P, Delzescaux T, et al. Characterization of hyperinsulinism in infancy assessed with PET and 18F-Fluoro-L-DOPA. J Nucl Med 2005;46:560–566.

27 Multimodal Imaging Using PET and MRI Thomas Pfluger and Klaus Hahn

Magnetic resonance imaging (MRI) and positron emission tomography (PET) are diagnostic imaging modalities that facilitate visualization of morphologic as well as functional features of different diseases in childhood. Both modalities are often used separately or even in competition. Some of the most important indications for both PET and MRI lie in the field of pediatric oncology. The malignant diseases in children are leukemia, brain tumors, lymphomas, neuroblastoma, soft tissue sarcomas, Wilms’ tumor, and bone sarcomas. Apart from leukemia, correct assessment of tumor expansion with modern imaging techniques, mainly consisting of ultrasonography, computed tomography (CT), MRI, and PET, is essential for cancer staging, for the choice of the best therapeutic approach, and for restaging after therapy or in recurrence (1,2).

Indications for MRI in Children Magnetic resonance imaging is an excellent tool for noninvasive evaluation of tumor extent, and it has become the study of choice for evaluating therapy-induced regression in the size of musculoskeletal sarcomas. It directly demonstrates the lesion in relationship to surrounding normal structures with exquisite anatomic detail (3,4). Especially in children, MRI offers several fundamental advantages compared to CT examinations and other whole-body imaging modalities, such as the absence of radiation exposure; the nonuse of iodinated, potential nephrotoxic contrast agents; a high intrinsic contrast for soft tissue and bone marrow; and accurate morphologic visualization of internal structure. All of these advantages are decisive factors in tumor staging (5–7). Due to its much higher intrinsic soft tissue contrast compared to CT, MRI has been shown to be advantageous in neuroradiologic, musculoskeletal, cardiac, and oncologic diseases (2,6). On the other hand, CT plays a major role in the assessment of 485

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thoracic lesions and masses due to a lower frequency of movement artifacts. Because structural abnormalities are detected with high accuracy, MRI generally has a high sensitivity for detecting structural alterations but a low specificity for further characterization of these abnormalities (8). Frequently, these structural abnormalities are not reliable indicators of viable tumor tissue, especially after treatment (4). T2-weighted MRI sequences visualize fluid-equivalent changes with high sensitivity. This is of special importance in detection of cysts and edema in the diagnosis of inflammatory and tumorous diseases. High signal intensity on T1-weighted MRI sequences facilitates the differentiation of adipose tissue and hemorrhage. Depiction of soft tissue or lesion perfusion can be achieved by the use of paramagnetic contrast agents like gadolinium–diethylenetriamine pentaacetic acid (Gd-DTPA). Modern fast and ultrafast sequences permit monitoring of contrast medium perfusion over time, which improves recognition of lesions. These rapid sequences are especially widespread in contrast-enhanced MR angiography (MRA), which provides high-resolution selective arterial and venous vascular imaging. A further improvement in the contrast medium effect has been achieved by suppression of the signal from adipose tissue in T1-weighted sequences. These fat-suppressed, contrast-enhanced sequences are currently considered “state of the art” in the workup of tumors and inflammatory processes.

Necessary Components for Multimodality Imaging Three basic components are required for multimodal imaging. First, multiple imaging modalities, often including one nuclear medical [PET, single photon emission computed tomography (SPECT)] and one radiologic (CT, MRI) cross-sectional imaging method, must be available. Second, there must be simple and prompt access to the corresponding images or image data sets. Adequate multimodal imaging requires a clinic-wide computer network, a digital archive of radiologic and nuclear medical studies, multimodal image viewing workstations, and appropriate software for image correlation and fusion (9,10). These requirements are currently satisfied to only a limited extent in hospital departments of radiology and nuclear medicine and in private practices. Third, and probably most important, is the competence of the physician in evaluating these different nuclear medical and radiologic data sets. Because each individual modality can yield false-negative findings, a careful and time-consuming separate analysis of each individual modality prior to multimodal processing is essential. In combined multimodal image evaluation, there is a tendency to depend primarily on the findings of PET, which usually identifies pathologic processes more rapidly. In doing so, one runs the risk of missing diagnoses that would be seen on MRI because of the reliance on falsenegative PET scans. Therefore, a mainly PET-guided analysis of MRI should be avoided.

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Algorithms and Accuracy of Combined Image Analysis and Image Registration The retrospective registration and superimposition of multimodal image data can be done using different approaches and algorithms, which, in general, can be broken down into feature- and volume-based techniques. The image transformation can be static (displacement and rotation in all three spatial axes) or nonlinear (e.g., additional stretching or compression in order to compensate for respiratory movements) (11). The classic example of a feature-based method is the “surface matching” or Pelizzari algorithm, which uses organ surfaces as a property (12). The disadvantages of this technique are the requirement for a potentially quite extensive segmentation of the organ surface in the different modalities and the fact that image registration is based on only the extracted portions of the image (surface pixels). Simply stated, volume-based techniques analyze similarities of pixel distribution in the two imaging modalities (11). The representative of this algorithm group enjoying the widest current application is the “mutual information” algorithm in which two-dimensional gray-scale histograms of the individual modalities and a combined histogram are analyzed and compared in various image transformations (13,14). Advantages of the volume-based techniques include the fully automatic application, their robustness compared to a different “field of view,” and the higher degree of precision in image registration (11). A meta-analysis by Hutton and Braun (10) quantified the exactness of software-based cerebral image registration at less than 3 mm (10). For extracerebral applications, the PET and CT registration of pulmonary focal lesions showed a comparable exactness (average position of center of the lesion) of 6.2 mm for separate modalities (15) and of 7.6 mm for combined PET/CT scanners (16).

Analysis and Presentation of Multimodality Images The evaluation of multimodal imaging data consists of three stages. The first stage corresponds to the separate analysis of the multimodal data in nuclear medicine and diagnostic radiology with subsequent comparison of the reported findings. In the case of discrepancies, a separate reevaluation of the imaging data is performed with comparison of the other imaging modality. This is currently the most widely used method, and it has the advantage of minimum requirements in terms of hardware and software, together with restricted logistic, temporal, and personnel requirements. The very great disadvantage is the lack of an exact anatomic-functional comparison of both methods. This disadvantage can be decisive in the recognition and delineation of physiologic changes. The second stage consists of simultaneous interpretation of the multimodal data sets at the same site. Although this is possible using conventional films, it is more practicable when performed at viewing workstations having picture archiving and communication system (PACS) access. Although this method enhances the capacity for

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Figure 27.1. Multimodality display on a Hermes workstation (Nuclear Diagnostics AB, Haegersten, Sweden) demonstrating a left-sided paravertebral lymph node metastasis from a yolk sack tumor on magnetic resonance imaging (MRI) (left image) and positron emission tomography (PET) (right image).

morphologic correlation, because of the associated significant increase in personnel, cost, and time requirements, it is advisable to progress directly to the third stage. In the third stage, analysis of spatially synchronized image data is performed simultaneously at a single workstation (Fig. 27.1). Synchronization may be interactive or partially or fully automatic with help of a fusion algorithm (17). These conditions provide for optimum spatial correlation of findings. Also useful is a common cursor that points to the corresponding location in both modalities, which are displayed side by side (11). This exact synchronization of data sets with appropriate software provides the additional capacity for image fusion with superimposition of both sets of imaging data in one image. In addition, a three-dimensional reconstruction of the fused imaging data can be used for therapy planning (Fig. 27.2, see color insert). When Figure 27.2. Three-dimensional (3D) reconstruction of a registered image data set. The cortical surface was rendered from MRI and red dots represent subdural EEG electrodes that were imaged with CT. The functional epileptogenic focus (orange) was defined by interictal fluorodeoxyglucose (FDG)-PET and ictal ECD– single photon emission computed tomography (SPECT). (See color insert.)

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using a fused image, it is important to note that original information from the two individual imaging modalities may be partially lost, meaning that the original images of each modality should also be simultaneously displayed (Fig. 27.3, see color insert) (11). Following image analysis comes the presentation of multimodal images to one’s clinical colleagues, for whom the display of the fused imaging data sets moves to the foreground. Here, image fusion and three-dimensional reconstruction often represent decisive building blocks for understanding the pathology and for further therapeutic planning (Fig. 27.2). Combination of MRI and PET In combined imaging, morphologic information from MRI is complemented and extended by the functional information supplied by PET about glucose metabolism of the respective lesions. An important advantage of fluorodeoxyglucose (FDG)-PET, especially in the staging of malignant disease, is the capacity for examining the entire body or whole-body regions, whereas MRI is usually able to image only fractions of the same area during a single session (Fig. 27.4). Most publications of clinical applications and usefulness of multimodal diagnostic imaging concern oncologic imaging and multimodal diagnosis of epilepsy (7,18–27). The major concentration of fluorine-18 (18F)-FDG-PET is in oncologic diagnostics, where the evaluation of glucose metabolism in the tumor provides information on its viability. For this reason, PET in many cases has a higher specificity, sometimes even a higher sensitivity, than morphologic imaging modalities (MRI and CT) (28–33). Furthermore, a review of the literature shows PET imaging to be suitable for the majority of pediatric malignancies (1,34–42). Advances in these two anatomic and functional diagnostic imaging technologies have significantly influenced the staging and treatment approaches for pediatric tumors (8,38). The methods provide complementary information and have become essential in modern cancer therapy. Thus, anatomic and functional noninvasive technologies should be viewed as complementary rather than competitive. To identify a change in function without knowing accurately where it is localized, or, equivalently, to know there is an anatomic change without understanding the nature of the underlying cause compromises the clinical efficacy of both anatomic and functional imaging techniques (8,38,43). Combination of whole-body PET and state-of-the-art MRI offers accurate registration of metabolic and molecular aspects of a disease with exact correlation to anatomic findings, improving the diagnostic value of PET and MRI in identifying and characterizing malignancies and in tumor staging. Positron emission tomography can be used to detect areas of malignancies, tumor growth, therapeutic response, and recurrence. Malignancies with low or normal metabolic activity may show clearly positive or suspicious findings in the MRI (6). In a comparative study demonstrating the potential of combined PET-MRI diagnostics in 42 pediatric examinations, the sensitivity and specificity in detecting viable tumor

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C Figure 27.3. Histologically proven nonaffected cystic ovary in a patient with a recurrent yolk sack tumor: T1-weighted, fat-suppressed MR sequence after application of gadolinium–diethylenetriamine pentaacetic acid (Gd-DTPA) (A) depicts a physiologic-appearing cystic ovary (arrow). Corresponding PET (B) revealed a false-positive finding with an increased glucose uptake (arrow) suspect of a recurrent disease. Multimodality display of registered images (C) shows exact spatial correlation between the cystic ovary in MRI and increased glucose uptake in PET. (See color insert.)

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were significantly increased with combined analysis (44). The main reasons for false-positive PET findings when looking at suspected solitary tumor lesions in children are inflammatory or reactive changes in lymph nodes without tumor infiltration, normal bone marrow after chemotherapy, and physiologic FDG uptake of the intestine, the ovary (Fig. 27.3), the ureter, and brown adipose tissue. False-negative findings in FDG-PET primarily occur in bone metastases and tumoraffected lymph nodes due to low glucose metabolism or small size (Fig. 27.5). One reason is the limited spatial resolution of PET, which leads to false-negative findings in very small lesions (45). Under chemotherapy, active bone metastases may temporarily become PET-negative (Table 27.1) (35). In MRI, the main reasons for false-positive findings are enlarged lymph nodes and bone marrow edema without tumor involvement.

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B Figure 27.5. Histologically proven metastases of a Ewing sarcoma in the proximal femoral bone on both sides. A: T1-weighted fat-suppressed MR sequence shows hypointense lesions within the bone (arrows). B: Corresponding PET revealed a false-negative finding with no signs of metastatic spread in either femoral bone.

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Table 27.1. Possible sources of false-positive and false-negative findings in MRI and FDG-PET False-positive PET:

False-positive MRI: False-negative PET: False-negative MRI:

Brown adipose tissue; physiologic uptake in the muscles, bowel, ureter, and ovary; inflammatory changes (i.e., in lymph nodes); normal bone marrow after chemotherapy Posttherapeutic changes (i.e., persisting bone marrow edema in treated metastases), enlarged lymph nodes without tumor affection Metastases with a small size and/or low glucose metabolism, tumor lesions under chemotherapy Small lymph node and bone metastases, lesions in the neighborhood of the bowel

Small bone and lymph node metastases can also be responsible for false-negative findings. Tumor lesions adjacent to normal bowel structures quite often cannot be distinguished from the bowel and consequently cannot be detected with MRI (Fig. 27.6). In the diagnosis of lymph nodes, a diameter of more than 1 cm is the leading parameter for the diagnosis of a metastasis. Therefore, lymph node metastases smaller than this and reactive lymph node enlargement are misinterpreted. Lesion size is not a reliable parameter for metastatic involvement (46). After successful tumor therapy, bone marrow edema often persists for a long time in MRI and may be responsible for falsepositive findings. In summary, MRI is highly sensitive, but not very specific (Table 27.1) (35,45,47,48). When combining FDG-PET and MRI in pediatric oncology, PET as a whole-body imaging tool plays a major role in assessing MRI-positive lesions. The most important benefit of MRI is to distinguish PETpositive tumor lesions from physiologically increased glucose uptake. In addition, MRI is indispensable for surgical and biopsy planning (Fig. 27.7). The combination of PET and MRI improves the diagnostic value of PET and MRI in identifying and characterizing tumor tissue, respectively (4,6,49). Positron emission tomography is also used in the workup of inflammatory disease, though far less frequently than for oncologic indications. It is the method of choice in the search for a focus of inflammation in a patient with fever of unknown origin and/or unclear sepsis (50–54). Lesions detected with PET can be further delineated with MRI, which may also be useful for further therapy planning. 18 F-fluorodeoxyglucose-PET is also very useful in the presurgical focus localization in the workup of epilepsy. An exact integration of the findings of morphologic, electrophysiologic, and nuclear medical examinations is of great importance in the planning of surgical procedures for the treatment of epilepsy and for determination of the borders of resection, again underscoring the role of integrative diagnostics (55,56). In patients with epilepsy, functional diagnostic methods include EEG and nuclear medical methods for visualizing cerebral metabolism and

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B Figure 27.6. Recurrent tumor of a rhabdomyosarcoma lateral and superior to the urine bladder (arrows) in a 6-year-old boy. This recurrent lesion cannot be distinguished from the adjacent bowel either in T2-weighted MRI (A) or in the T1-weighted sequence after application of Gd-DTPA (B), thereby leading to a false-negative finding. PET clearly depicts an increased glucose metabolism in the corresponding region resulting in true-positive finding (C). Furthermore, postoperative metal artifacts in the right proximal femoral bone can be seen in MRI (A,B). PET and MRI show a metastasis of the left proximal femoral bone as well.

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C Figure 27.6. Continued.

perfusion. Frequently, ictal technetium-99m ECD-SPECT is combined with interictal FDG-PET, which permits more exact identification of the seizure focus with typical hypometabolism seen on PET (57–60). Beside conventional EEG leads, subdural electrodes may be implanted prior to the actual surgical procedure for direct measurement of the EEG signal from the cortical surface. These subdural electrodes can also be used for cortical stimulation. This permits delineation of functionally important areas that must be protected during a resective procedure. Knowledge of the exact position of the individual electrode points is important for demarcation of the resection boundaries. Because only CT can visualize these electrode points with sufficient accuracy, integration of CT information into the combined PET-MRI analysis is also necessary (56). Demarcation of resection boundaries, therefore, requires integration of all four described modalities: MRI for brain morphology, CT to establish the position of the subdural EEG electrodes, PET for visualization of brain metabolism, and SPECT for visualization of hyperperfusion. This is best achieved with three-dimensional image fusion, which permits exact spatial integration (Fig. 27.2). Here, registration of images is possible within 1.5 mm, which is adequate for clinical application (61). This method has also been shown to be superior to localization of electrodes using a conventional radiograph (56). The resulting reconstructed three-dimensional data set provides the neurosurgeon with the information needed for exact preoperative planning, including functional information on the focus of the seizure and important (especially language-related) brain areas that must be protected during resection.

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Figure 27.7. Rhabdomyosarcoma of the lower abdomen in a 6-year-old boy. A: FDG-PET demonstrates a large area with increased glucose uptake correlating to the primary tumor and a central photopenic defect (arrowheads). B: This photopenic defect correlates well to central necrosis visible in the T1weighted, contrast-enhanced MR sequence (arrowheads). C: For operative planning, a T2-weighted short-time inversion recovery (STIR) sequence is necessary for the delineation of tumor borders and course of vessels.

Conclusion It is important to emphasize that MRI and PET are not competing modalities. Instead, these two methods in combination can produce a synergy between function and morphology. For planning of biopsies and resective surgery, the knowledge of function (i.e., tumor viability) provided by PET and of the exact morphology of the tumor provided by MRI is often crucial. In patients with cerebral lesions, the whole spectrum of digital image fusion with direct superimposition of several modalities and subsequent three-dimensional reconstruction should be applied. This provides the surgeon with the tools for exact planning of approach and resection boundaries. Direct image superimposition is not necessary for extracranial questions because information from individual modalities may be partially lost during fusion. The simultaneous evaluation of both modalities is to be emphasized. Having corresponding slices from both modalities displayed at a single workstation for synchronized evaluation is very

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C Figure 27.7. Continued.

useful. This is the most reliable method of immediately and efficiently correlating pathologic and especially unclear findings with the corresponding slice on the other imaging method. Because of MRI’s low specificity in oncologic staging and at follow-up monitoring, the addition of PET for evaluating tumor vitality is essential.

References 1. Connolly LP, Drubach LA, Ted Treves S. Applications of nuclear medicine in pediatric oncology. Clin Nucl Med 2002;27(2):117–125. 2. Schmidt GP, Baur-Melnyk A, Tiling R, Hahn K, Reiser MF, Schoenberg SO. Comparison of high resolution whole-body MRI using parallel imaging and PET-CT. First experiences with a 32–channel MRI system. Radiologe 2004;44(9):889–898.

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Chapter 27 Multimodal Imaging Using PET and MRI 3. Bloem JL, van der Woude HJ, Geirnaerdt M, Hogendoorn PC, Taminiau AH, Hermans J. Does magnetic resonance imaging make a difference for patients with musculoskeletal sarcoma? Br J Radiol 1997;70(832):327–337. 4. Bredella MA, Caputo GR, Steinbach LS. Value of FDG positron emission tomography in conjunction with MR imaging for evaluating therapy response in patients with musculoskeletal sarcomas. AJR 2002;179(5): 1145–1150. 5. Antoch G, Vogt FM, Bockisch A, Ruehm SG. Whole-body tumor staging: MRI or FDG-PET/CT? Radiologe 2004;44(9):882–888. 6. Gaa J, Rummeny EJ, Seemann MD. Whole-body imaging with PET/MRI. Eur J Med Res 2004;9(6):309–312. 7. Pfluger T, Schmied C, Porn U, et al. Integrated imaging using MRI and 123I metaiodobenzylguanidine scintigraphy to improve sensitivity and specificity in the diagnosis of pediatric neuroblastoma. AJR 2003;181(4): 1115–1124. 8. Czernin J. Clinical applications of FDG-PET in oncology. Acta Med Austriaca 2002;29(5):162–170. 9. Alyafei S, Inoue T, Zhang H, et al. Image fusion system using PACS for MRI, CT, and PET images. Clin Positron Imaging 1999;2(3):137–143. 10. Hutton BF, Braun M. Software for image registration: algorithms, accuracy, efficacy. Semin Nucl Med 2003;33(3):180–192. 11. Slomka PJ. Software approach to merging molecular with anatomic information. J Nucl Med 2004;45(suppl 1):36S–45S. 12. Pelizzari CA, Chen GT, Spelbring DR, Weichselbaum RR, Chen CT. Accurate three-dimensional registration of CT, PET, and/or MR images of the brain. J Comput Assist Tomogr 1989;13(1):20–26. 13. Maes F, Collignon A, Vandermeulen D, Marchal G, Suetens P. Multimodality image registration by maximization of mutual information. IEEE Trans Med Imaging 1997;16(2):187–198. 14. Wells WM 3rd, Viola P, Atsumi H, Nakajima S, Kikinis R. Multi-modal volume registration by maximization of mutual information. Med Image Anal 1996;1(1):35–51. 15. Skalski J, Wahl RL, Meyer CR. Comparison of mutual information-based warping accuracy for fusing body CT and PET by 2 methods: CT mapped onto PET emission scan versus CT mapped onto PET transmission scan. J Nucl Med 2002;43(9):1184–1187. 16. Cohade C, Osman M, Marshall LN, Wahl RN. PET-CT: accuracy of PET and CT spatial registration of lung lesions. Eur J Nucl Med Mol Imaging 2003;30(5):721–726. 17. Stokking R, Zubal IG, Viergever MA. Display of fused images: methods, interpretation, and diagnostic improvements. Semin Nucl Med 2003; 33(3):219–227. 18. Aquino SL, Asmuth JC, Alpert NM, Halpern EF, Fischman AJ. Improved radiologic staging of lung cancer with 2-(18F)-fluoro-2-deoxy-D-glucosepositron emission tomography and computed tomography registration. J Comput Assist Tomogr 2003;27(4):479–484. 19. Cohade C, Wahl RL. Applications of positron emission tomography/ computed tomography image fusion in clinical positron emission tomography—clinical use, interpretation methods, diagnostic improvements. Semin Nucl Med 2003;33(3):228–237. 20. Coleman RE, Hawk TC, Hamblen SM, Laymon CM, Turkington TG. Detection of recurrent brain tumor. Comparison of MR registered camera-based and dedicated PET images. Clin Positron Imaging 1999;2(1):57–61.

T. Pfluger and K. Hahn 21. Dresel S, Grammerstorff J, Schwenzer K, et al. (18F)FDG imaging of head and neck tumours: comparison of hybrid PET and morphological methods. Eur J Nucl Med Mol Imaging 2003;30(7):995–1003. 22. Keidar Z, Israel O, Krausz Y. SPECT/CT in tumor imaging: technical aspects and clinical applications. Semin Nucl Med 2003;33(3):205–218. 23. Murphy M, O’Brien TJ, Morris K, Cook MJ. Multimodality image-guided epilepsy surgery. J Clin Neurosci 2001;8(6):534–538. 24. So EL. Role of neuroimaging in the management of seizure disorders. Mayo Clin Proc 2002;77(11):1251–1264. 25. Tsai CC, Tsai CS, Ng KK, et al. The impact of image fusion in resolving discrepant findings between FDG-PET and MRI/CT in patients with gynaecological cancers. Eur J Nucl Med Mol Imaging 2003;21:21. 26. Visvikis D, Ell PJ. Impact of technology on the utilisation of positron emission tomography in lymphoma: current and future perspectives. Eur J Nucl Med Mol Imaging 2003;30(suppl 1):S106–116. 27. Zhang W, Simos PG, Ishibashi H, et al. Multimodality neuroimaging evaluation improves the detection of subtle cortical dysplasia in seizure patients. Neurol Res 2003;25(1):53–57. 28. Anderson H, Price P. What does positron emission tomography offer oncology? Eur J Cancer 2000;36(16):2028–2035. 29. Bar-Shalom R, Valdivia AY, Blaufox MD. PET imaging in oncology. Semin Nucl Med 2000;30(3):150–185. 30. Czech N, Brenner W, Kampen WU, Henze E. [Diagnostic value of positron emission tomography (PET) in clinical oncology.] Dtsch Med Wochenschr 2000;125(18):565–567. 31. Delbeke D, Martin WH. Positron emission tomography imaging in oncology. Radiol Clin North Am 2001;39(5):883–917. 32. Mankoff DA, Bellon JR. Positron-emission tomographic imaging of cancer: glucose metabolism and beyond. Semin Radiat Oncol 2001;11(1): 16–27. 33. Scott AM. Current status of positron emission tomography in oncology. Intern Med J 2001;31(1):27–36. 34. Brisse H, Ollivier L, Edeline V, et al. Imaging of malignant tumours of the long bones in children: monitoring response to neoadjuvant chemotherapy and preoperative assessment. Pediatr Radiol 2004;34(8):595–605. 35. Daldrup-Link HE, Franzius C, Link TM, et al. Whole-body MR imaging for detection of bone metastases in children and young adults: comparison with skeletal scintigraphy and FDG PET. AJR 2001;177(1): 229–236. 36. Franzius C, Daldrup-Link HE, Wagner-Bohn A, et al. FDG-PET for detection of recurrences from malignant primary bone tumors: comparison with conventional imaging. Ann Oncol 2002;13(1):157–160. 37. Hawkins DS, Rajendran JG, Conrad EU 3rd, Bruckner JD, Eary JF. Evaluation of chemotherapy response in pediatric bone sarcomas by (F-18)fluorodeoxy-D-glucose positron emission tomography. Cancer 2002;94(12): 3277–3284. 38. Hudson MM, Krasin MJ, Kaste SC. PET imaging in pediatric Hodgkin’s lymphoma. Pediatr Radiol 2004;34(3):190–198. 39. Montravers F, McNamara D, Landman-Parker J, et al. ((18)F)FDG in childhood lymphoma: clinical utility and impact on management. Eur J Nucl Med Mol Imaging 2002;29(9):1155–1165. 40. O’Hara SM, Donnelly LF, Coleman RE. Pediatric body applications of FDG PET. AJR 1999;172(4):1019–1024.

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Chapter 27 Multimodal Imaging Using PET and MRI 41. Shulkin BL. PET imaging in pediatric oncology. Pediatr Radiol 2004;34(3): 199–204. 42. Shulkin BL, Mitchell DS, Ungar DR, et al. Neoplasms in a pediatric population: 2–(F-18)-fluoro-2–deoxy-D-glucose PET studies. Radiology 1995; 194(2):495–500. 43. Townsend DW, Cherry SR. Combining anatomy and function: the path to true image fusion. Eur Radiol 2001;11(10):1968–1974. 44. Pfluger T, Vollmar C, Porn U, et al. Combined PET/MRI in cerebral and pediatric diagnostics. Der Nuklearmediziner 2002;25(2):122–127. 45. Hueltenschmidt B, Sautter-Bihl ML, Lang O, et al. Whole body positron emission tomography in the treatment of Hodgkin disease. Cancer 2001; 91(2):302–310. 46. Torabi M, Aquino SL, Harisinghani MG. Current concepts in lymph node imaging. J Nucl Med 2004;45(9):1509–1518. 47. Ilias I, Pacak K. Current approaches and recommended algorithm for the diagnostic localization of pheochromocytoma. J Clin Endocrinol Metab 2004;89(2):479–491. 48. Korholz D, Kluge R, Wickmann L, et al. Importance of F18–fluorodeoxyD-2–glucose positron emission tomography (FDG-PET) for staging and therapy control of Hodgkin’s lymphoma in childhood and adolescence— consequences for the GPOH-HD 2003 protocol. Onkologie 2003;26(5): 489–493. 49. Popperl G, Lang S, Dagdelen O, et al. Correlation of FDG-PET and MRI/ CT with histopathology in primary diagnosis, lymph node staging and diagnosis of recurrency of head and neck cancer. Rofo 2002;174(6):714– 720. 50. Blockmans D, Knockaert D, Maes A, et al. Clinical value of ((18)F)fluorodeoxyglucose positron emission tomography for patients with fever of unknown origin. Clin Infect Dis 2001;32(2):191–196. 51. Kapucu LO, Meltzer CC, Townsend DW, Keenan RJ, Luketich JD. Fluorine18–fluorodeoxyglucose uptake in pneumonia. J Nucl Med 1998;39(7): 1267–1269. 52. Kresnik E, Mikosch P, Gallowitsch HJ, Heinisch M, Lind P. F-18 fluorodeoxyglucose positron emission tomography in the diagnosis of inflammatory bowel disease. Clin Nucl Med 2001;26(10):867. 53. Meller J, Becker W. [Nuclear medicine diagnosis of patients with fever of unknown origin (FUO).] Nuklearmedizin 2001;40(3):59–70. 54. Weiner GM, Jenicke L, Buchert R, Bohuslavizki KH. [FDG PET for the localization diagnosis in inflammatory disease of unknown origin—two case reports.] Nuklearmedizin 2001;40(4):N35–38. 55. Barnett GH, Kormos DW, Steiner CP, Morris H. Registration of EEG electrodes with three-dimensional neuroimaging using a frameless, armless stereotactic wand. Stereotact Funct Neurosurg 1993;61(1):32–38. 56. Winkler PA, Vollmar C, Krishnan KG, Pfluger T, Brückmann H, Noachtar S. Usefulness of 3–D reconstructed images of the human cerebral cortex for localization of subdural electrodes in epilepsy surgery. Epilepsy Res 2000;41(7):169–178. 57. Carreras JL, Perez-Castejon MJ, Jimenez AM, Domper M, Montz R. [Neuroimaging in epilepsy. Advances in SPECT and PET in epilepsy.] Rev Neurol 2000;30(4):359–363. 58. Matheja P, Kuwert T, Stodieck SR, et al. PET and SPECT in medically non-refractory complex partial seizures. Temporal asymmetries of glucose consumption, benzodiazepine receptor density, and blood flow. Nuklearmedizin 1998;37(7):221–226.

T. Pfluger and K. Hahn 59. Noachtar S, Arnold S, Yousry TA, Bartenstein P, Werhahn KJ, Tatsch K. Ictal technetium-99m ethyl cysteinate dimer single-photon emission tomographic findings and propagation of epileptic seizure activity in patients with extratemporal epilepsies. Eur J Nucl Med 1998;25(2):166– 172. 60. Oliveira AJ, da Costa JC, Hilario LN, Anselmi OE, Palmini A. Localization of the epileptogenic zone by ictal and interictal SPECT with 99mTc-ethyl cysteinate dimer in patients with medically refractory epilepsy. Epilepsia 1999;40(6):693–702. 61. Pfluger T, Vollmar C, Wismuller A, et al. Quantitative comparison of automatic and interactive methods for MRI-SPECT image registration of the brain based on 3-dimensional calculation of error. J Nucl Med 2000; 41(11):1823–1829.

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28 Current Research Efforts Fabio Ponzo and Martin Charron

Over the past 20 years, as clinical applications have been gradually expanding, positron emission tomography (PET) has become an indispensable imaging technique in several medical fields such as oncology, neurology, and cardiology. Application of PET in pediatrics is still very limited, likely due to the smaller number of clinical reports involving PET in pediatric as compared to adult medicine and to the lesser availability of PET scanners in pediatric facilities. However, the recent expansion of the regional availability of the most common PET radiotracer, fluorine-18 fluorodeoxyglucose (18F-FDG) and, more importantly, the recent appearance of the dual-modality PET–computed tomography(CT) imaging system have provided new opportunities of expansion of PET to the pediatric field. The recent mechanical coupling of CT to PET in the same imaging device for attenuation correction permits precise localization of metabolic findings on anatomic images and shortens the total acquisition time. Both qualities are particularly important in pediatric imaging, making the study more acceptable to patients and parents and less cumbersome for personnel. Moreover, the shortened acquisition time reduces the probability of motion artifacts on reconstructed images. This chapter briefly summarizes the state of clinical applications of PET in the pediatric field and discusses potential new research approaches and new clinical applications of PET and PET-CT in pediatric patients.

Patient Preparation Preparation of children and parents for PET imaging is critical, and its importance has already been the object of discussion (1,2). The importance of NPO (nothing by mouth) status for 4 to 6 hours prior to FDG administration needs to be emphasized and coordinated with family members and personnel taking care of the pediatric patient, especially in the case of children on total parenteral nutrition or undergoing chemotherapeutic therapy intravenously if dextrose is present in the intravenous fluids. Reliable intravenous access is fundamental, and 502

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bladder catheterization is needed to avoid reconstruction artifacts in the pelvis and the possibility of voiding and contamination during image acquisition (3,4). Sedation protocols vary, and several guidelines are available (5–7). Sedatives may affect cerebral metabolism but sometimes are required for completion of the study because light sedation is rarely helpful (8). Especially in case of sedated patients, PET-CT devices are quite valuable; spiral CT takes less than a minute, and the three-dimensional (3D) mode of acquisition of emission data reduces the emission imaging time to 4 to 5 minutes per bed position. Moreover, CT scans performed for attenuation correction are obtained with reduced milliamperes (mA), decreasing the absorbed dose to the patient without loss of image quality. Imaging protocols for PET-CT are a compromise between the desired combination of CT scans of different portions of the body and the patient’s tolerance. For this reason, the acquisition of CT images for the purpose of attenuation correction follows a simpler protocol (9–13). For example, PET-CT scans are done with free breathing, in contrast to diagnostic CT examination of the chest, which is often performed with the breath-hold technique. Breath holding with PET-CT can contribute to misregistration between CT and PET data. Both intravenous and oral contrast can be used in pediatrics with PET-CT without significant untoward effects on image quality. Oral contrast must be taken with sugar-free beverages to avoid competition in uptake of FDG and cannot be administered before the PET-CT study in case of general anesthesia. Contrast can improve interpretation of PET-CT images when evaluating small children with limited retroperitoneal fat (14,15), although semiquantitative measures such as the standard uptake value (SUV) may be affected (15–17). Future studies are needed to compare the diagnostic accuracy of PET-CT scans done after administration of intravenous (IV) or oral contrast and nonenhanced PET-CT scans. Better delineation of blood vessels may be critical in some cases, such as in lymphomas where better delineation of involved lymph nodes may result in a change in patient management. Administration of IV contrast may cause artifacts, especially in the lower neck, a region already complicated by the common presence of activated brown fat in children. The timing between contrast injection and imaging must be carefully observed on a patient-by-patient basis. Possible effects on SUV analysis by contrast dye still need to be evaluated.

Neurology Normal Brain Development The first structures to show glucose metabolism immediately after birth are the sensorimotor cortex, thalamus, brainstem, and cerebellar vermis, followed by the basal ganglia and the parietal, temporal, calcarine, and cerebellar cortices in the next 3 months of life and the frontal cortex and the dorsolateral cortex during the second 6 months of life (18–20).

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Recently, co-registration of PET and magnetic resonance imaging (MRI) has allowed identification of fetal organs and demonstrated that 18 F-FDG readily crosses the placenta and that 18F accumulates in both maternal and fetal brain in a nonhuman primate animal model. This study demonstrates the potential for noninvasively measuring the transfer of drugs across the placenta and for measuring the fetal drug distribution (21). Epilepsy Nearly all studies in children with epilepsy have been performed during interictus, given the relatively short half-life of 18F. The approximately 30-minute uptake time of FDG may also depict a combination of the areas of seizure propagation and the actual seizure focus. Nevertheless, in patients with continuous or frequent seizures, ictal PET has been shown to be able to localize extratemporal seizures (22). Interictal FDG-PET has proven useful in the localization of the epileptogenic region, which is indicated by regional hypometabolism (22,23). Among the available imaging modalities, FDG-PET is superior to CT and MRI alone in preoperative evaluation when combined with EEG data (22,24–26). Results from FDG-PET also have good correlation with those of MR spectroscopy (27). Poor prognosis has been associated with bitemporal hypometabolism on FDG-PET. These patients are typically not candidates for resective surgery (28–31). Children with infantile spasms may also benefit from evaluation with FDG-PET (32). Other PET radiotracers have also been applied in epilepsy diagnosis. Reduced uptake of carbon-11 (11C)flumazenil and of 11C-labeled (S)-(N-methyl)-ketamine corresponds to the epileptogenic region. A relative increase in uptake of 11C-carfentanil and 11C-deprenyl may also help in identifying epileptogenic foci (33–39). In patients with tuberous sclerosis, a-11C–methyl-L-tryptophan may also differentiate between epileptogenic and nonepileptogenic tubers (40). 6-18F-L-3,4-Fluorodihydroxyphenylalanine (18F-fluoro-L-DOPA) recently has been shown to be a promising agent in evaluation of control circuits of epilepsy. 18F-fluoro-L-DOPA permits measurements of presynaptic dopaminergic function and has been frequently used in studies of Parkinson’s disease. In drug-resistant epileptic patients with ring chromosome 20, 18F-fluoro-L-DOPA has shown involvement of the basal ganglia (41). The role of dopamine function in other types of drug-resistant epileptic syndromes has been recently evaluated by Bouilleret et al. (42). In an experimental study, three groups of children, the first composed of drug-resistant epileptic patients with ring chromosome 20, the second composed of patients with resistant, generalized “absence-like” epilepsy, and the third composed of patients with drug-resistant temporal lobe epilepsy with hippocampal sclerosis, were studied with 18Ffluoro-L-DOPA PET. The researchers used two strategies of analysis of the 18F-fluoro-L-DOPA uptake in basal ganglia: a multiple-time

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graphical analysis with regions of interest, and an all-brain statistical parametric mapping analysis using a voxel-by-voxel statistical t-test. Each epileptic group was compared with a group of healthy volunteers. The results showed that a decrease of uptake value was observed in the striatum in all groups of patients with both types of analysis. Multiple-time graphical analysis showed a reduction of uptake over each basal ganglion in both generalized (groups 1 and 2) and focal (group 3) epilepsies, confirming the involvement of the basal ganglia in patients with r20 epilepsy. More interestingly, a unilateral decrease of uptake was detected using statistical parametric mapping (SPM) analysis. This decrease was ipsilateral to the seizure side in patients with focal temporal lobe epilepsy. Moreover, SPM analysis showed a decrease of 18F-fluoro-LDOPA uptake in the substantia nigra bilaterally. This result confirms the involvement of dopamine neurotransmission in seizure control and demonstrates that this involvement is not specific to epileptic patients with ring chromosome 20. Further studies are needed to determine whether the decrease of 18F-fluoro-L-DOPA uptake is a cause or a consequence of seizures and to evaluate the specific role of substantia nigra in the control of different forms of seizures. The dopamine system modulation may have a potential role in controlling epileptic foci; this opens new possibilities of pharmacologic treatment of drug-resistant epilepsy (42). Cerebral Inflammatory Diseases Rasmussen’s encephalitis in infants has been investigated using FDGPET. It is characterized by unilateral cerebral decreased FDG uptake corresponding to regions of cerebral atrophy seen at MRI, increasing the specificity of MRI findings (43,44). Abnormal FDG uptake may also precede clinical symptoms in HIV-1–infected children born to seropositive mothers (45). Other Neurologic Applications In term newborns, perinatal asphyxia may cause hypoxic-ischemic encephalopathy, which has been studied with FDG PET. The impairment of cerebral glucose metabolism correlates well with the severity of encephalopathy and short-term clinical outcome (40,46–48). A change in cerebral glucose metabolism has been demonstrated in other childhood brain disorders such as traumatic brain injury, autism, attention-deficit/hyperactivity disorder, schizophrenia, sickle cell encephalopathy, and anorexia and bulimia nervosa (49–57). Prader-Willi syndrome (PWS) has been recently studied with FDGPET (58). This syndrome is a neurogenetic disorder caused by lack of expression of paternal genes in the 15q11-q13 region, and is the most common form of human syndromic obesity. Along with compulsive hyperphagia, children affected with PWS present hypothalamic hypogonadism and mental retardation. In this study, nine children affected

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with PWS underwent resting brain FDG-PET, and the results showed decreased glucose metabolism in regions associated with taste perception and food reward such as the superior temporal gyrus and insula. There was increased FDG uptake in areas involved in cognitive functions related to eating or obsessive-compulsive behavior such as the orbitofrontal and middle frontal gyrus, left cingulate gyrus, and right uncus. Interestingly, the hypothalamus, the brain region usually involved in energy intake, did not show abnormal metabolism. Patients with hereditary spastic paraplegia (HSP), a rare hereditary autosomal-recessive disorder, suffer slowly progressive retrograde axonal degeneration of the corticospinal tracts and dorsal columns. Symptoms are ataxia, dysarthria, unipolar depression, epilepsy, migraine, and cognitive impairment. The disease is linked to the SPG4 locus on chromosome 2p (59). Oxygen-15–radiolabeled water (15OH2O) PET has been used to study regional cerebral blood flow in patients with HSP. 15O-H2O PET showed significantly relative decreased blood flow in frontotemporal and thalamic regions at rest. Ongoing studies are being performed for the evaluation of cerebral activation response after motor stimuli.

Cardiology Only a few papers have been published investigating the role of PET in pediatric cardiology (60,61). Positron emission tomography with nitrogen-13 (13N)-ammonia has been employed to measure myocardial perfusion in infants after anatomic repair of congenital heart defects and after Norwood palliation for hypoplastic left heart syndrome (62,63). Positron emission tomography has also been used to assess myocardial blood flow and impaired coronary flow reserve after coronary reimplantation in patients with Fontan-like operations (64,65). Gated FDG-PET has been proved useful in the evaluation of regional glucose metabolism and contractile function in children after arterial switch operation and suspected myocardial infarction (66). In children with Kawasaki disease, combined assessment of cardiac flow and metabolism with PET showed abnormalities in more than 40% of patients during the acute and the convalescent stage of disease (67). Positron emission tomography with 11C-acetate has demonstrated reduced Krebs’ cycle activity in children with mitochondrial cardiomyopathy despite normal myocardial perfusion (68).

Inflammatory Disease Potential new application of FDG-PET in the study of inflammatory diseases can be hypothesized because FDG accumulation is not specific for tumors. Neutrophils and macrophages also exhibit increased glucose metabolism at the site of inflammation and infection. At the present time, only a limited number of publications address the role of FDG-PET in detecting inflammatory diseases in infants and children.

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Fluorodeoxyglucose-PET was proven useful in the assessment of children with suspected inflammatory bowel disease (69). Potential advantages of FDG-PET include its noninvasiveness, its repeatability, and its capability to localize the segment involved and to quantify disease activity in view of the assessment of therapeutic efficacy. The sensitivity and accuracy of FDG-PET have not yet been compared with those of other diagnostic techniques such as abdominal ultrasound, small bowel follow through, and endoscopy/histology. However, FDG-PET has already demonstrated higher sensitivity than CT in detecting active infective foci in children with chronic granulomatous disease (70). Other authors have reported the clinical usefulness of FDG-PET in detecting occult infectious foci (71), identifying infectious mononucleosis lesions (72), and monitoring therapy in patients with aspergillosis (73). An overview of the literature with regard to the value of PET in pediatric lung diseases was published by Richard et al. (74). In acute pneumonia, neutrophils are the primary cell type responsible for the increase in 18F-FDG tissue uptake, 10 to 40 times above values obtained in normal subjects (75–78). 18 F-Fluorodeoxyglucose-PET has shown different rates of glucose uptake in the lungs in different patient groups, despite the presence of airway neutrophilia in each, according to the presence of acute or chronic inflammatory disease (75,79,80). More reliable quantification of pulmonary inflammation than the mere number of neutrophils present in the tissue has also been obtained in experimental allergen-induced airway inflammation in asthmatics (81) and in a neonatal model of acute lung injury in piglets (82) using FDG-PET. Cystic fibrosis (CF) is the most common inherited disease of Caucasians; it is autosomal recessive and occurs in approximately 1 in 2500 to 3000 live births. The life expectancy of a child born with CF has gradually improved and is now approaching 32 years (83). The morbidity and mortality in this disease result from airway infection and inflammation. The intense and persistent host inflammatory response is thought to account for progressive, suppurative pulmonary disease (84), the neutrophils being the prominent inflammatory cells (85). Only preliminary data are available regarding the use of FDG-PET in CF (86), but a recent report has compared the ability of FDG-PET in monitoring disease activity in children with CF (87). At the present time bronchoalveolar lavage is the only available method to quantify airway inflammation directly, but it is invasive and samples only limited volume of the lungs. Preliminary data from Chen et al. (87) have shown that the calculated plasma/activity ratio from a dynamic PET scan on a region of interest placed over the entire lung positively correlates with the mean neutrophil count from bronchoalveolar lavage. Therefore, FDG-PET seems to be an effective, noninvasive tool to measure neutrophilic inflammation in CF. It may also have an important role in monitoring the response to therapy, as already reported in the setting of sarcoidosis treated with corticosteroids (88). It might be also useful as a noninvasive method of testing new antiinflammatory therapies in children with inflammatory lung disease.

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Oncology Potential Causes of Misinterpretation of FDG-PET in Children Fluorodeoxyglucose distribution may be altered in children because of areas of physiologically increased glucose metabolism; this is particularly evident in the thymus (89,90) and in the skeletal growth centers, mostly in the long bone physes. As in adults, other potential pitfalls include variable FDG uptake in working skeletal muscles, brown fat, myocardium, thyroid gland, and the gastrointestinal tract. Fluorodeoxyglucose is also always present in the renal pelvis, ureters, and bladder because of its renal excretion (91–95). To decrease the incidence of interfering brown fat activity, the use of pharmacologic interventions has been described: propranolol or reserpine treatment seems to reduce FDG uptake (96); diazepam in low doses shows no effectiveness (97). The recent use of PET-CT has significantly decreased the incidence of false-positive findings on PET, given the precise anatomic correlation of metabolic evidences on PET images. The most common equivocal areas on PET that can be further clarified as nonmalignant by PET-CT include brown fat, bowel, thymus muscle, ureters, stomach, and esophagus (98). To further enhance the specificity of PET-CT, the use of intravenous contrast has been proposed but there is still insufficient evidence in the literature to support its use (99–101). Recent preliminary data have instead compared PET-CT with contrast enhanced CT in children with lymphoma (102). The authors have reported discrepant findings between the two techniques, mostly related to metabolically active subcentimeter lymph nodes and residual soft tissue in the mediastinum negative on PET-CT. Further studies are needed to compare the diagnostic accuracy of contrast-enhanced CT with non–contrast-enhanced PET-CT and to evaluate the impact of possible added value of contrastenhanced CT over PET-CT on patient management. Diffuse high FDG uptake in bone marrow and spleen following administration of hematopoietic stimulating factors (103,104) and of granulocyte colony-stimulating factor may also cause misinterpretation of FDG accumulation (103). Chemotherapy may also cause thymus hyperplasia with relative increased FDG metabolism (89,105). The coregistration technique of the new combined PET-CT imaging systems may also cause artifacts that are not limited to pediatric patients; they are caused by metallic objects, respiration, and oral and intravenous contrast agents (106). Central Nervous System Tumors Magnetic resonance imaging and CT are now the imaging modalities used for staging and follow-up of children with central nervous system (CNS) tumors, but the role of PET has been increasing in recent years. Increased FDG uptake can help distinguish viable tumor from posttherapeutic sclerotic changes (107–109) and correlates well with histopathology and clinical data (110–113). Preoperative planning,

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including a combination of MRI and PET data, improves the diagnostic yield of stereotactic brain biopsy in pediatric brain tumors and reduces tissue sampling in high-risk functional areas (114,115). In children affected by neurofibromatosis type 1 who have low-grade astrocytomas, FDG-PET has good correlation with clinical outcome (116). Fluorodeoxyglucose uptake in brain tumors can be a better predictor of tumor growth than histopathology (117). Other positronemitting tracers such as 18F-a-methyltyrosine (118), 11C-methionine (119), and 11C-thymidine (120) have been reported to be useful in the study pediatric brain tumors. Recent initial results with O-(2-18Ffluorethyl)-L-tyrosine (FET)-PET in 44 patients with primary bone tumors seem to indicate that tumor uptake is higher in high-grade tumors, and different uptake kinetics of FET may help in identifying a highly aggressive brain lesion (121). A possible future application of PET in the evaluation of recurrent tumor may take advantage of the possibility of co-registration between PET images and MR images. The co-registration technique has been used already to improve the anatomic localization of metabolically active sites in pediatric tumors (122). Moreover, further characterization may be obtained using co-registration between metabolic information obtained with FDG-PET and anatomic and metabolic data obtained with proton magnetic resonance spectroscopy (MRS) imaging. Additional studies are still needed to compare enhanced glucose metabolism and choline/lactate ratios in brain tumors with different degrees of aggressiveness. Lymphoma and Leukemia Non-Hodgkin’s and Hodgkin’s lymphomas are the third most common type of malignancy in childhood, accounting for between 10% and 15% of pediatric malignancies. Lymphoblastic and small-cell tumors are the most common histologic types of non-Hodgkin’s lymphoma. Nodular sclerosing and mixed cellularity are the most common histologic types of Hodgkin’s disease. In adult patients, FDG has been shown to accumulate in non-Hodgkin’s and Hodgkin’s lymphomas (91,123–146), with more intense uptake in higher-grade lymphomas than in lowergrade lymphomas (130,132). Fluorodeoxyglucose-PET has been reported to be highly effective in evaluating lymphomatous involvement for staging and patient management (127,128,133,134,147). Fluorodeoxyglucose uptake also has excellent predictive value for patient outcome in the follow-up period (148). Fluorodeoxyglucose-PET is useful in identifying the site of biopsy or in eliminating the need for biopsy at staging (128,140) and in assessing activity in posttherapy residual soft tissue masses (134,142). The co-registration between PET and CT in the new PET-CT devices has been effective in the evaluation of lymphoma. A recent report found that 75% of FDG-PET-CT studies provided further information on patient disease status (149). In summary, PET plays an increasingly important role in staging, evaluating tumor response, planning radiation treatment fields, and

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monitoring after completion of therapy in pediatric lymphoma (150–152). In he future, FDG-PET-CT may function as primary imaging modality in these patients. In addition, possible deficits of glucose metabolism after cranial radiation therapy have been studied with FDG-PET in children treated for acute lymphoblastic leukemia. Quantification of cerebral glucose uptake provided by PET demonstrated significant changes after cranial radiation therapy (153). Neuroblastoma Neuroblastoma is the most common extracranial solid malignant tumor in children. Up to 70% of patients have disseminated neuroblastoma at presentation. Proper staging is critical because localized neuroblastoma may be treated with surgery with or without preoperative chemotherapy, according to the degree of the local extension. Distant metastases are indicative of poor prognosis. Magnetic resonance imaging, CT, bone scintigraphy, and scintigraphy with meta-iodobenzylguanidine (mIBG) or indium-111-pentetreotide are currently used in clinical practice for the evaluation of disseminated disease (154). Neuroblastomas are metabolically active tumors that avidly concentrate FDG. However, FDG-PET has been shown to have disconcordant results when compared to mIBG and is not proved to be a better imaging technique in the delineation of residual disease (155). Therefore, at present, the primary role of FDG-PET is in the evaluation of known or suspected neuroblastomas that do not demonstrate mIBG uptake. Children with high-risk neuroblastomas after resection of the primary tumor and in the absence or resolution of skull lesions may also be monitored using FDG-PET and bone marrow examinations without performing additional diagnostic tests (156). The use of other radiopharmaceutical such as 11C-hydroxyephedrine, 11 C-epinephrine, 18F-3-iodobenzylguanidine, 18F-fluoronorepinephrine, 18 F-flurometaraminol, 18F-fluorodopamine, and iodine-124 (124I)-mIBG have also been described as being useful in evaluating neuroblastoma (157–159). Wilms’ Tumor Wilms’ tumor is the most common renal malignancy of childhood, typically presenting as an asymptomatic abdominal mass. Other imaging modalities such as radiography, ultrasonography, CT, and MRI are commonly used in the definition of the local extent of Wilms’ tumor in kidneys and soft tissue and in the detection of metastases. Fluorodeoxyglucose-PET has a limited role in the anatomic staging of primary tumor, given the renal excretion of FDG and the limited spatial resolution of PET. A potential role of FDG-PET is in the follow-up after radiation or chemotherapy for identification of residual disease (160). Bone Tumors Osteosarcoma and Ewing’s sarcoma are the two primary bone malignancies of childhood. The treatment of choice for primary bone malig-

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nancies of an extremity is wide resection and limb-sparing surgery with chemotherapy pre- and postoperatively. Magnetic resonance imaging is currently used in anatomic staging of primary bone malignancies. However, MRI has shown variable results in assessing chemotherapeutic response (161–166). The exact role of FDG-PET in osteosarcoma and Ewing’s sarcoma is unclear. Semiquantification of FDG uptake using SUV analysis has been reported to provide useful information for the differentiation between benign and malignant bone tumors (167,168). Several articles have evaluated the role of FDG-PET in comparison with other diagnostic techniques in the evaluation of metastatic disease in bone tumors. In a comparison of whole-body MRI, whole-body bone scan, and FDG-PET, Daldrup-Link et al. (169) have found the highest sensitivity for FDG-PET in the detection of osseous metastases from primary bone tumors. Franzius et al. (170) found spiral CT to be superior to FDG-PET in detecting pulmonary metastases and FDG-PET to be more sensitive, specific, and accurate than bone scintigraphy in identifying osseous metastases from Ewing’s sarcoma. However, FDGPET was less sensitive than bone scan for detecting metastases from osteosarcoma (171). For detection of recurrences from malignant primary bone tumors, Franzius et al. (172) also found FDG-PET to have higher sensitivity, specificity, and accuracy than conventional imaging modalities. Current experience suggests that, in patients with bone sarcomas, FDG-PET may play an important role in monitoring response to preoperative neoadjuvant chemotherapy (173–176). A decrease of FDG uptake in response to neoadjuvant chemotherapy correlates well with histopathologic findings and with disease-free survival after therapy. As an alternative to bone scintigraphy and FDG-PET, the use of PET and PET-CT with 18F-FNa (sodium fluoride) has been proposed by Even-Sapir et al. in assessing malignant osseous involvement and in differentiating malignant from benign bone lesions (177). In a series of 44 patients, the authors found 18F-fluoride PET-CT both sensitive and specific for the detection of lytic and sclerotic malignant lesions. Positron emission tomography–CT also differentiated malignant from benign bone lesions, and, for most lesions, the anatomic data provided by the low-dose CT of the PET-CT study obviates the need for full-dose diagnostic CT for correlation purposes. The role of PET-CT with 18FFNa has not yet been evaluated in the pediatric population with bone tumors. Osseous metastasis is the main adverse prognostic factor in patients with Ewing tumors. Recently, to evaluate osseous metastasis, a highresolution animal PET scanner has been tested on an experimental mouse model for human Ewing tumor metastases. Both glucose metabolism and bone metabolism were assessed using 18F-FDG and 18F-FNa. Osteolytic lesions showed decreased 18F-FNa uptake and increased 18FFDG uptake. The experimental mouse model and the high-resolution animal PET scanner may be used in future for the evaluation of new tracers for the diagnosis and monitoring of experimental therapies of Ewing tumor (178).

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Rhabdomyosarcoma is the most common soft tissue malignancy of childhood. It can develop in any organ or tissue, most commonly in the head and neck and the genitourinary tract. Computed tomography or MRI is important for local staging. Radiation therapy and surgery are used to control local disease. Radiography, CT, and skeletal scintigraphy are used to identify metastases, which are treated with chemotherapy. Rhabdomyosarcomas show FDG uptake, and FDG-PET has been reported to have more clinical utility than standard imaging evaluation (8,173,179). In soft tissue sarcomas, FDG-PET was able to distinguish high-grade soft tissue sarcoma from low-grade or benign tumors (180). Comparing the results of FDG-PET, MRI, and CT in 62 patients with soft tissue sarcomas, Lucas et al. (181) showed FDG-PET to be the best stand-alone modality for the assessment of local tumor recurrence and distant metastases. For the evaluation of local recurrent disease in patients with musculoskeletal sarcomas, MRI has a prominent role. However, Bredella et al. (182) recently showed FDG-PET to be a useful adjunct to MRI in distinguishing viable tumor from scar tissue. Pheochromocytoma Pheochromocytoma and paraganglioma may occur at any age, but they are most common from early to mid-adulthood. For localization of primary tumor, MRI and CT are the diagnostic techniques in use. Scintigraphy with 131I-mIBG has limited sensitivity. A possible role of PET in the staging and restaging of pheochromocytoma and paraganglioma has been hypothesized using 6-18F-fluorodopamine. Preliminary results show that this technique is highly sensitive in pheochromocytoma localization (183). Metastatic adrenal cortical carcinoma has very poor prognosis (184). The most common locations for distant metastases are the lung, liver, and skeleton. The preferred imaging methods (CT and MRI) are the screening methods for the most common lung and liver metastases (185). Fluorodeoxyglucose-PET imaging in adults seems to be able to differentiate malignant from benign adrenal lesions (186,187). Recently, a different cost-effective and noninvasive approach has been proposed in the evaluation of adrenocortical carcinomas in children: primary screening with PET, followed by morphologic imaging with CT or MRI (188). Hepatoblastoma Hepatoblastoma is a rare hepatic tumor of children. It is generally treated with surgical resection with perioperative use of chemotherapy. Posttreatment follow-up is generally achieved with serial monitoring of a-fetoprotein (AFP) levels and conventional radiologic imaging. Early detection of recurrent hepatoblastoma is not always possible with conventional imaging methods such as CT and MRI. Philip et al. (189) have recently described the use of FDG-PET to locate the site of recurrence in the follow-up of three cases of pediatric

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patients with elevated AFP levels (189). In the first two patients, FDGPET accurately located recurrent disease where it was not detected by conventional imaging modalities, including CT and MRI. In the third patient, FDG-PET imaging also located the recurrent disease in an MRIidentified adrenal metastasis. The technique of co-registration of PET with CT and MRI scans improved the anatomic localization of metabolically active sites and was particularly useful for determining the surgical approach. The results of this study seem to confirm the value of PET-CT and other co-registration techniques in the evaluation of early tumor recurrence or metastatic disease in hepatoblastoma. Additional studies are needed to evaluate the impact of FDG-PET-CT imaging in patient management.

Conclusion The routine clinical use of PET in pediatric patients is still limited. This is partly because PET scanning in children is only supported when applicable to similar reimbursed adult conditions. Positron emission tomography–CT applications are still viewed with caution given the additional radiation dose delivered by the CT device used for attenuation purpose. Moreover, the number of pediatric institutions able to offer PET or PET-CT studies is still limited. Few pediatric centers can use cyclotron facilities, animal scanners, and dedicated personnel and researchers in the development of new radiotracer or devices suitable for pediatric diseases. However, given the actual conditions, it is remarkable to see the growing interest in pediatric applications of PET and the increasing number of clinical research projects involving PET in pediatric diseases. It is conceivable that in the future this number will rise even more, given the fast-growing importance PET-CT in the evaluation of adult neoplastic and inflammatory diseases. Finally, there is still need for a multiinstitutional, cooperative effort in this endeavor. A joint approach may help in the collection of data from different institutions and in directing combined efforts toward the most promising studies and applications.

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Chapter 28 Current Research Efforts 116. Molloy PT, Defeo R, Hunter J, et al. Excellent correlation of FDG-PET imaging with clinical outcome in patients with neurofibromatosis type I and low grade astrocytomas. J Nucl Med 1999;40:129P. 117. Jadvar H, Alavi A, Mavi A, Shulkin BL. PET imaging in pediatric diseases. Radiol Clin North Am 2005;43:135–152. 118. Inoue T, Shibasaki T, Oriuchi N, et al. 18F-alpha-methyl tyrosine PET studies in patients with brain tumors. J Nucl Med 1999;40:399–405. 119. Utriainen M, Metsahonkala L, Salmi TT, et al. Metabolic characterization of childhood brain tumors: comparison of 18F-fluorodeoxyglucose and 11C-methionine positron emission tomography. Cancer 2002;95:1376– 1386. 120. Vander Borght T, Pauwels S, Lambotte L, et al. Brain tumor imaging with PET and 2-(carbon-11)thymidine. J Nucl Med 1994;35:974–982. 121. Weckesser M, Langen KJ, Rickert CH, et al. Initial experiences with O-(2(18F)-fluorethyl)-L-tyrosine PET in the evaluation of primary bone tumors. Presented at the 51st annual meeting of the Society of Nuclear Medicine Meeting 2004:513. 122. Philip I, Shun A, McCowage G, Howman-Giles R. Positron emission tomography in recurrent hepatoblastoma. Pediatr Surg Int 2005;21(5):341– 345. 123. Barrington SF, Carr R. Staging of Burkitt’s lymphoma and response to treatment monitored by PET scanning. Clin Oncol 1995;7:334–335. 124. Bangerter M, Moog F, Buchmann I, et al. Whole-body 2–(18F)-fluoro-2deoxy-D-glucose positron emission tomography (FDG-PET) for accurate staging of Hodgkin’s disease. Ann Oncol 1998;9:1117–1122. 125. Jerusalem G, Warland V, Najjar F, et al. Whole-body 18F-FDG-PET for the evaluation of patients with Hodgkin’s disease and non-Hodgkin’s lymphoma. Nucl Med Commun 1999;20:13–20. 126. Leskinen-Kallio S, Ruotsalainen U, Nagren K, et al. Uptake of carbon-11methionine and fluorodeoxyglucose in non-Hodgkin’s lymphoma: a PET study. J Nucl Med 1991;32:1211–1218. 127. Moog F, Bangerter M, Kotzerke J, et al. 18-F-fluorodeoxyglucose positron emission tomography as a new approach to detect lymphomatous bone marrow. J Clin Oncol 1998;16:603–609. 128. Moog F, Bangerter M, Diederichs CG, et al. Extranodal malignant lymphoma: detection with FDG-PET versus CT. Radiology 1998;206:475–481. 129. Moog F, Bangerter M, Diederichs CG, et al. Lymphoma: role of wholebody 2-deoxy-2-(F-18)fluoro-D-glucose (FDG) PET in nodal staging. Radiology 1997;203:795–800. 130. Okada J, Yoshikawa K, Imazeki K, et al. The use of FDG-PET in the detection and management of malignant lymphoma: correlation of uptake with prognosis. J Nucl Med 1991;32:686–691. 131. Okada J, Yoshikawa K, Itami M, et al. Positron emission tomography using fluorine-18–fluorodeoxyglucose in malignant lymphoma: a comparison with proliferative activity. J Nucl Med 1992;33:325–329. 132. Rodriguez M, Rehn S, Ahlstrom H, et al. Predicting malignancy grade with PET in non-Hodgkin’s lymphoma. J Nucl Med 1995;36:1790–1796. 133. Newman JS, Francis IR, Kaminski MS, et al. Imaging of lymphoma with PET with 2-(F-18)-fluoro-2-deoxy-D-glucose: correlation with CT. Radiology 1994;190:111–116. 134. de Wit M, Bumann D, Beyer W, et al. Whole-body positron emission tomography (PET) for diagnosis of residual mass in patients with lymphoma. Ann Oncol 1997;8(suppl 1):57–60.

F. Ponzo and M. Charron 135. Cremerius U, Fabry U, Neuerburg J, et al. Positron emission tomography with 18-F-FDG to detect residual disease after therapy for malignant lymphoma. Nucl Med Commun 1998;19:1055–1063. 136. Hoh CK, Glaspy J, Rosen P, et al. Whole-body FDGPET imaging for staging of Hodgkin’s disease and lymphoma. J Nucl Med 1997;38:343– 348. 137. Romer W, Hanauske AR, Ziegler S, et al. Positron emission tomography in non-Hodgkin’s lymphoma: assessment of chemotherapy with fluorodeoxyglucose. Blood 1998;91:4464–4471. 138. Stumpe KD, Urbinelli M, Steinert HC, et al. Whole-body positron emission tomography using fluorodeoxyglucose for staging of lymphoma: effectiveness and comparison with computed tomography. Eur J Nucl Med 1998;25:721–728. 139. Lapela M, Leskinen S, Minn HR, et al. Increased glucose metabolism in untreated non-Hodgkin’s lymphoma: a study with positron emission tomography and fluorine-18-fluorodeoxyglucose. Blood 1995;86:3522– 3527. 140. Carr R, Barrington SF, Madan B, et al. Detection of lymphoma in bone marrow by whole-body positron emission tomography. Blood 1998;91: 3340–3346. 141. Segall GM. FDG-PET imaging in patients with lymphoma: a clinical perspective. J Nucl Med 2001;42(4):609–610. 142. Moody R, Shulkin B, Yanik G, et al. PET FDG imaging in pediatric lymphomas. J Nucl Med 2001;42(5 suppl):39P. 143. Kostakoglu L, Leonard JP, Coleman M, et al. Comparison of FDG-PET and Ga-67 SPECT in the staging of lymphoma. Cancer 2002;94(4):879– 888. 144. Lin PC, Chu J, Pocock N. F-18 fluorodeoxyglucose imaging with coincidence dual-head gamma camera (hybrid FDG-PET) for staging of lymphoma: comparison with Ga-67 scintigraphy. J Nucl Med 2000;41(5 suppl): 118P. 145. Tomas MB, Manalili E, Leonidas JC, et al. F-18 FDG imaging of lymphoma in children using a hybrid pet system: comparison with Ga-67. J Nucl Med 2000;41(5 suppl):96P. 146. Tatsumi M, Kitayama H, Sugahara H, et al. Whole-body hybrid PET with 18F-FDG in the staging of non-Hodgkin’s lymphoma. J Nucl Med 2001;42(4):601–608. 147. Körholz D, Kluge R, Wickmann L, et al. Importance of F18-fluorodeoxyD-2-glucose positron emission tomography (FDG-PET) for staging and therapy control of Hodgkin’s lymphoma in childhood and adolescence— consequences for the GPOH-HD 2003 protocol. Onkologie 2003;26:489– 493. 148. Klein M, Fox M, Kopelewitz B, et al. Role of FDG PET in the follow up of pediatric lymphoma. Presented at the 51st annual meeting of the Society of Nuclear Medicine 2004:378. 149. Tatsumi M, Miller JH, Wahl RL. Initial assessment of the role of FDG PET in pediatric malignancies. Presented at the 51st annual meeting of the Society of Nuclear Medicine 2004:383. 150. Hudson MM, Krasin MJ, Kaste SC. PET imaging in pediatric Hodgkin’s lymphoma. Pediatr Radiol 2004;34:190–198. 151. Krasin MJ, Hudson MM, Kaste SC. Positron emission tomography in pediatric radiation oncology: integration in the treatment-planning process. Pediatr Radiol 2004;34:214–221.

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Chapter 28 Current Research Efforts 152. Franzius C, Schober O. Assessment of therapy response by FDG-PET in pediatric patients. Q J Nucl Med 2003;47(1):41–45. 153. Kahkonen M, Metsahonkala L, Minn H, et al. Cerebral glucose metabolism in survivors of childhood acute lymphoblastic leukemia. Cancer 2000;88:693–700. 154. Briganti V, Sestini R, Orlando C, et al. Imaging of somatostatin receptors by indium-111-pentetreotide correlates with quantitative determination of somatostatin receptor type 2 gene expression in neuroblastoma tumor. Clin Cancer Res 1997;3:2385–2391. 155. Shulkin BL, Hutchinson RJ, Castle VP, et al. Neuroblastoma: positron emission tomography with 2- (fluorine-18)-fluoro-2-deoxy-D-glucose compared with metaiodobenzylguanidine scintigraphy. Radiology 1996; 199:743–750. 156. Kushner BH, Yeung HW, Larson SM, et al. Extending positron emission tomography scan utility to high risk neuroblastoma: fluorine-18 fluorodeoxyglucose positron emission tomography as sole imaging modality in follow-up of patients. J Clin Oncol 2001;19:3397–3405. 157. Shulkin BL, Wieland DM, Castle VP, et al. Carbon-11 epinephrine PET imaging of neuroblastoma. J Nucl Med 1999;40:129P. 158. Vaidyanathan G, Affleck DJ, Zalutsky MR. Validation of 4-(fluorine-18) fluoro-3-iodobenzylguanidine as a positron-emitting analog of MIBG. J Nucl Med 1995;36:644–650. 159. Ott RJ, Tait D, Flower MA, et al. Treatment planning for 131I-mIBG radiotherapy of neural crest tumors using 124I-mIBG positron emission tomography. Br J Radiol 1992;65:787–791. 160. Shulkin BL, Chang E, Strouse PJ, et al. PET FDG studies of Wilms’ tumors. J Pediatr Hematol Oncol 1997;19:334–338. 161. Frouge C, Vanel D, Coffre C, et al. The role of magnetic resonance imaging in the evaluation of Ewing sarcoma—a report of 27 cases. Skeletal Radiol 1988;17:387–392. 162. MacVicar AD, Olliff JFC, Pringle J, et al. Ewing sarcoma: MR imaging of chemotherapy-induced changes with histologic correlation. Radiology 1992;184:859–864. 163. Lemmi MA, Fletcher BD, Marina NM, et al. Use of MR imaging to assess results of chemotherapy for Ewing sarcoma. AJR 1990;155:343– 346. 164. Erlemann R, Sciuk J, Bosse A, et al. Response of osteosarcoma and Ewing sarcoma to preoperative chemotherapy: assessment with dynamic and static MR imaging and skeletal scintigraphy. Radiology 1990;175:791– 796. 165. Holscher HC, Bloem JL, Vanel D, et al. Osteosarcoma: chemotherapyinduced changes at MR imaging. Radiology 1992;182:839–844. 166. Lawrence JA, Babyn PS, Chan HS, et al. Extremity osteosarcoma in childhood: prognostic value of radiologic imaging. Radiology 1993;189:43– 47. 167. Watanabe H, Shinozaki T, Yanagawa T, et al. Glucose metabolic analysis of musculoskeletal tumours using 18fluorine-FDG PET as an aid to preoperative planning. J Bone Joint Surg Br 2000;82:760–767. 168. Wu H, Dimitrakopoulou-Strauss A, Heichel TO, et al. Quantitative evaluation of skeletal tumours with dynamic FDG PET: SUV in comparison to Patlak analysis. Eur J Nucl Med 2001;28:704–710. 169. Daldrup-Link HE, Franzius C, et al. Whole-body MR imaging for detection of bone metastases in children and young adults: comparison with skeletal scintigraphy and FDG PET. AJR 2001;177:229–236.

F. Ponzo and M. Charron 170. Franzius C, Daldrup-Link HE, Sciuk J, et al. FDG-PET for detection of pulmonary metastases from malignant primary bone tumors: comparison with spiral CT. Ann Oncol 2001;12:479–486. 171. Franzius C, Sciuk J, Daldrup-Link HE, et al. FDG-PET for detection of osseous metastases from malignant primary bone tumours: comparison with bone scintigraphy. Eur J Nucl Med 2000;27:1305–1311. 172. Franzius C, Daldrup-Link HE, Wagner-Bohn A, et al. FDG-PET for detection of recurrences from malignant primary bone tumors: comparison with conventional imaging. Ann Oncol 2002;13:157–160. 173. Lenzo NP, Shulkin B, Castle VP, et al. FDG-PET in childhood soft tissue sarcoma. J Nucl Med 2000;41(5 suppl):96P. 174. Abdel-Dayem HM. The role of nuclear medicine in primary bone and soft tissue tumors. Semin Nucl Med 1997;27:355–363. 175. Shulkin BL, Mitchell DS, Ungar DR, et al. Neoplasms in a pediatric population: 2-(F-18)-fluoro-2-deoxy-D-glucose PET studies. Radiology 1995; 194:495–500. 176. Hawkins DS, Rajendran JG, Conrad III EU, et al. Evaluation of chemotherapy response in pediatric bone sarcomas by (F-18)-fluorodeoxy-D-glucose positron emission tomography. Cancer 2002;94:3277–3284. 177. Even-Sapir E, Metser U, Flusser G, et al. Assessment of malignant skeletal disease: initial experience with 18F-fluoride PET/CT and comparison between 18F-fluoride PET and 18F-fluoride PET/CT. J Nucl Med 2004; 45:272–278. 178. Franzius C, Hotfilder M, Hermann S, et al. Feasibility of high resolution animal PET of Ewing tumors and their metastasis in a NOD/SCID mouse model. Presented at the 51st annual meeting of the Society of Nuclear Medicine 2004:382. 179. Ben Arush MW, Israel O, Kedar Z, et al. Detection of isolated distant metastasis in soft tissue sarcoma by fluorodeoxyglucose positron emission tomography: case report. Pediatr Hematol Oncol 2001;18(4):295– 298. 180. Lucas JD, O’Doherty MJ, Cronin BF, et al. Prospective evaluation of soft tissue masses and sarcomas using fluorodeoxyglucose positron emission tomography. Br J Surg 1999;86:550–556. 181. Lucas JD, O’Doherty MJ, Wong JC, et al. Evaluation of fluorodeoxyglucose positron emission tomography in the management of soft-tissue sarcomas. J Bone Joint Surg Br 1998;80:441–447. 182. Bredella MA, Caputo GR, Steinbach LS. Value of FDG positron emission tomography in conjunction with MR imaging for evaluating therapy response in patients with musculoskeletal sarcomas. AJR 2002;179: 1145–1150. 183. Pacak K, Eisenhofer G, Carrasquillo JA, et al. 18-6-(18F)fluorodopamine positron emission tomographic (PET) scanning for diagnostic localization of pheochromocytoma. Hypertension 2001;38:6–8. 184. Sabbaga CC, Avilla SG. Schulz C, et al. Adrenocortical carcinoma in children: clinical aspects and prognosis. J Pediatr Surg 1993;28:841–843. 185. Evans HL, Vassilopoulou-Sellin R. Adrenal cortical neoplasms. A study of 56 cases. Am J Clin Pathol 1996;105:76–86. 186. Maurea S, Mainolfi C, Wang H, et al. Positron emission tomography (PET) with fludeoxyglucose F 18 in the study of adrenal masses: comparison of benign and malignant lesions. Radiol Med 1996;92:782–787. 187. Boland GW, Goldberg MA, Lee MJ, et al. Indeterminate adrenal mass in patients with cancer: evaluation at PET with 2-(F-18)-fluoro2–deoxy-glucose. Radiology 1995;194:131–134.

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Section 5 Imaging Atlas

29 PET–Computed Tomography Atlas M. Beth McCarville

Fluorine-18-fluorodeoxyglucose (FDG) positron emission tomography (PET) is a functional imaging modality that capitalizes on the fact that pathologic processes are generally highly metabolically active and accumulate more glucose (and FDG) than normal tissue. However, sites of normal metabolic activity can also demonstrate intense FDG uptake and can sometimes be difficult to distinguish from disease activity. Fusion imaging modalities that acquire both functional and correlative anatomic imaging provide an important advantage over PET alone because they allow the accurate anatomic localization of sites of increased FDG activity (1–5). In this chapter, normal sites of FDG activity are correlated with computed tomography (CT) anatomy in images obtained during PET-CT scanning. Examples of pathologic FDG activity are included to illustrate the unique value of this fusion imaging modality in distinguishing normal from pathologic activity.

Head and Neck Identifying normal FDG activity in the head and neck, as elsewhere in the body, is aided by its bilaterally symmetric distribution. Because the brain is exclusively dependent on glucose metabolism, it accumulates intense FDG activity. Accumulation is greatest in the cerebral cortex, basal ganglia, thalamus, and cerebellum (Figs. 29.1 and 29.2). Intense activity is sometimes present, not only in the brain, but also in the ocular muscles and optic nerves (Fig. 29.2). Because FDG is known to accumulate in saliva (6,7), minimal to moderate activity may be present in the salivary and parotid glands (Fig. 29.3). Fluorodeoxyglucose uptake also occurs in the lymphatic tissues of the pharynx, specifically within the Waldeyer ring, which consists of the nasopharyngeal, palatine, and lingual tonsils (Fig. 29.3). In patients who are tense, FDG activity may be very prominent in the neck muscles secondary to contractioninduced metabolic activity. Fluorodeoxyglucose activity in the normal thyroid gland is usually absent or minimal but can be prominent. Intrinsic laryngeal muscles of phonation can exhibit intense FDG activity 527

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Figure 29.1. A,B: Axial positron emission tomography–computed tomography (PET-CT) images show fluorodeoxyglucose (FDG) activity in normal cerebral cortex (arrows), head of caudate (curved arrows), and thalami (arrowheads).

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Figure 29.2. A,B: Axial PET-CT images show FDG activity in normal optic nerves (arrowheads), temporal lobes (straight arrows), and cerebellum (curved arrows).

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Figure 29.3. A,B: Axial PET-CT images show FDG uptake in a normal Waldeyer ring (arrowheads) and normal parotid glands (arrows).

especially in patients who engage in speech activity immediately before or after the injection of FDG (Fig. 29.4) (7–9). To reduce such activity, patients should be encouraged to remain silent beginning 15 minutes prior to radioisotope injection until the imaging session is complete.

Chest Intense FDG activity is often present within brown adipose tissue in the supraclavicular regions, axilla, and paraspinal regions of the posterior mediastinum. The primary function of brown adipose tissue is

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Figure 29.4. A,B: Axial PET-CT images show normal FDG activity in the perilaryngeal tissues (arrows) often seen in patients who have engaged in speech after FDG injection.

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the production of heat. Brown fat differs from other tissues by the presence of an uncoupling protein within its mitochondria. This protein leads to a markedly reduced production of adenosine triphosphate (ATP) while increasing the oxidation of fatty acids to a maximal rate, resulting in the production of heat. During stimulated thermogenesis, glucose prevents this highly metabolic brown fat from becoming ATP-deprived by providing ATP through anaerobic glycolysis (10). Thermogenesis, therefore, leads to an accumulation of glucose and FDG within brown fat. Brown fat is known to be particularly metabolically active in pediatric patients, females, and persons with a low body mass index (10–12). Positron emission tomography–CT is especially useful in localizing sites of intense FDG activity in the supraclavicular regions because the CT will demonstrate either the absence (in the case of brown fat) or the presence of a soft tissue mass in the area of increased activity (Figs. 29.5 and 29.6). The thymus is located in the anterior mediastinum and extends from the thoracic inlet to the heart. Normal thymic FDG activity is homogeneous and may be minimal, moderate, or more intense than the mediastinal blood pool (Fig. 29.7). On CT the thymus has a quadrilateral-shaped configuration with homogeneous density. In

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Figure 29.5. A: Maximum intensity projection (MIP) image showing intense, symmetric activity in the supraclavicular regions (arrow). B,C: Axial PET-CT images allow localization of this activity to supraclavicular brown fat (arrows). This finding is common in pediatric patients.

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Figure 29.6. A 26-year-old woman with non-Hodgkin’s lymphoma. A,B: Axial PET-CT images show FDG activity in both supraclavicular brown fat (arrows) and pathologic supraclavicular nodes (arrowheads). This example illustrates the value of PET-CT in identifying adenopathy that may be difficult to distinguish from physiologic brown fat activity on PET alone.

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C Figure 29.7. A: MIP anterior PET image shows normal thymic contour and FDG activity (arrow) in a 3-year-old girl. B,C: Axial PET-CT images allow localization of activity to the thymus (arrows).

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Figure 29.8. A,B: Axial PET-CT images show typical intense FDG activity in a normal left ventricular myocardium (arrows).

early childhood, the lateral margins are slightly convex outward until adolescence when the thymus begins to involute and becomes more triangular in appearance. The normal thymus should have smooth margins and should never be nodular or lobulated (13). At about 1 hour after injection of FDG, blood pool activity in the mediastinum is moderate whereas lung activity is low. The heart has variable FDG avidity, usually with intense activity seen in the left ventricular myocardium (Fig. 29.8). Activity in the myocardium is dependent on serum insulin levels. When insulin levels are high, such as following a meal, the myocardium shifts from the metabolism of free-fatty acids to the glycolytic pathway, resulting in intense myocardial FDG activity (14,15). Fasting for 4 to 6 hours before the administration of FDG reduces both serum glucose and insulin availability, leading to decreased myocardial FDG activity. Minimal to moderate FDG activity may be present within the distal esophagus due to gastroesophageal reflux, muscle contraction, or inflammation (8,15).

Abdomen and Pelvis Fusion imaging is especially helpful in the abdomen and pelvis because sites of FDG activity can be difficult to localize accurately on PET alone, and sites that demonstrate abnormal FDG uptake may be overlooked on CT alone when the abnormality is subtle or unexpected (Fig. 29.9). In the upper abdomen, the cruces of the diaphragms and accessory muscles of respiration may demonstrate intense FDG activity, particularly in patients with increased work of breathing (Fig. 29.10) (8). There may be intense activity in the region of the adrenal glands within normal retroperitoneal brown fat. Liver activity is usually patchy but uniform in distribution without focal areas of intense activity. Splenic

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Figure 29.9. A,B: Axial PET-CT images show intense FDG activity within a metastatic deposit in the pancreas (arrows) of a 10-year-old girl with widely metastatic rhabdomyosarcoma. This pancreatic deposit was not clinically suspected and was overlooked on a CT scan performed 2 days earlier.

uptake is generally uniform and equal to or less than that of the liver (Figs. 29.10, 29.11, and 29.12). Fluorodeoxyglucose activity in the bowel is commonly seen but poorly understood. Postulated causes of bowel activity include smooth muscle contraction, metabolically active mucosa, uptake in lymphoid tissue, swallowed secretions containing FDG, and colonic microbial uptake (15–17). The stomach usually shows minimal to moderate activity within the fundus, although occasionally intense activity is seen

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Figure 29.10. A,B: Axial PET-CT images show normal FDG activity in the crus of the left diaphragm (straight arrows) and normal, homogeneous FDG uptake within the liver (curved arrows) and spleen (arrowheads). The spleen usually shows activity that is equal to or less than that of the liver.

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Figure 29.11. A,B: Axial PET-CT images show a focal area of abnormal activity that localizes to the liver (arrows). This was proven by biopsy to be metastatic Hodgkin’s lymphoma in this 12-year-old girl with ataxia-telangiectasia and Hodgkin’s lymphoma.

(Fig. 29.13). In these instances, correlating with CT imaging is useful in excluding obvious abnormalities within the stomach wall or to localize the activity to adjacent soft tissue abnormalities, such as adenopathy or pancreatic neoplasms. The degree of FDG activity in the small bowel and colon may be minimal, moderate, or intense and can be focal or diffuse (Fig. 29.14). Fluorodeoxyglucose activity in the small bowel and colon is often increased in patients who have fasted and is often most pronounced in the region of the cecum and right colon (15). The value of PET imaging in colorectal cancer is well established; however,

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Figure 29.12. A 17-year-old boy with stage IV Hodgkin’s disease. A,B: Axial PET-CT images show abnormal FDG activity in the spleen and nodes in the splenic hilum (straight arrows) and porta hepatis (curved arrows), consistent with lymphomatous involvement. Note that splenic activity is greater than the normal liver.

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Figure 29.13. A,B: Axial PET-CT images show moderate FDG activity in the wall of a normal stomach (arrows). Normal gastric FDG activity can vary from minimal to intense.

without correlative CT imaging, the findings of bowel activity on PET alone can be misleading. Computed tomography is useful in localizing the activity to the bowel and may demonstrate underlying bowel pathology such as a focal mass or an apple core lesion (Fig. 29.15). Even so, evaluation of the bowel by CT performed as part of a standard PETCT scan may be limited by the lack of oral or intravenous contrast material. If bowel pathology is a specific concern, the use of contrast agents may enhance lesion conspicuity. Fluorodeoxyglucose also accumulates in the glomerular filtrate but, unlike glucose, it is not resorbed in the renal tubules. This results in the intense accumulation of FDG in the renal collecting systems, ureters, and bladder (Fig. 29.16). The value of PET in evaluating the

Figure 29.14. MIP anterior image showing normal colonic activity (arrows).

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Figure 29.16. MIP anterior image of the abdomen shows the normal distribution of FDG activity in the kidneys (arrow), ureters (arrow), and urinary bladder (arrow).

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Figure 29.17. A,B: Axial PET-CT images show the normally intense activity seen in the kidneys (arrows) due to the accumulation of FDG in the glomerular filtrate.

kidneys is limited by the intense activity normally present within the renal collecting systems, which may obscure underlying abnormalities (Fig. 29.17). However, correlative PET-CT imaging may improve lesion conspicuity and localization of renal tumors. Intense FDG activity within the ureters is a common finding due to pooling of the radiotracer in the recumbent patient (8). Correlation with CT imaging allows distinction of the normal ureter from abnormal adjacent structures. Within the female pelvis, intense FDG activity may be present in normal ovaries and uteri, depending on the phase of the patient’s menstrual cycle (18). Positron emission tomography–CT is extremely useful in localizing FDG activity to these structures (Fig. 29.18). Activity within normal ovaries may not be bilaterally symmetric because the

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Figure 29.18. A,B: Axial PET-CT images show FDG activity within normal ovaries (arrows) in this 17year-old girl who was in remission from stage IIA Hodgkin’s disease. The degree of FDG uptake in the ovaries and uterus varies with menstrual phase. Normal ovarian activity may be asymmetric, as in this case.

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ovary containing the dominant follicle may be more physiologically active than the contralateral ovary. Correlation with the patients’ clinical history is useful in ruling out malignancy as an underlying cause of FDG uptake in the uterus and ovaries. In equivocal cases, follow-up PET-CT should show resolution or a diminution of FDG activity when the etiology is physiologic in nature (18). Within the male pelvis, activity in the normal testes can vary from minimal to intense, but should be bilaterally symmetric (Fig. 29.19).

Musculoskeletal Increased uptake of glucose into skeletal muscle is known to occur during muscle exercise (19). Likewise, the uptake of glucose, and hence FDG, into skeletal muscle is increased when muscle is electrically stimulated to undergo isometric contraction (19,20). The mechanism of glucose uptake into muscle is poorly understood, but it is distinct from the regulation of glucose metabolism by insulin. Increased blood flow and the translocation of glucose from the intracellular pool to the sarcolemmal membrane and activation of the protein carriers GLUT-1 and GLUT-4, in response to calcium released from the sarcoplasmic reticulum during muscle stimulation, may be responsible (19). When PET imaging reveals muscle FDG activity that is bilaterally symmetric (Fig. 29.20), it is likely due to increased glucose metabolism secondary to voluntary muscle contraction. Symmetric uptake of FDG in the neck and paravertebral muscles can be caused merely by patient anxiety. Administration of the muscle relaxant and anxiolytic agent diazepam has been effective in abolishing the high muscle FDG uptake seen in some patients (19). Asymmetric muscle activity can be due to the sequelae of local treatments such as surgery or radiation therapy or can be seen in a recently exercised muscle, even if the activity occurred prior to the

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Figure 29.19. A,B: Axial PET-CT images show bilaterally symmetric and intense activity in normal testes in this 19-year-old boy. The degree of FDG activity in normal testes can vary from minimal to intense but should be symmetric.

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Figure 29.20. Three-year-old boy with previously treated rhabdomyosarcoma of the left lower leg. A: MIP anterior image of the body shows symmetric activity in the forearm muscles (arrows). Note also the appearance of the normal bone marrow with increased activity in the growing physes of the proximal humeri (arrowhead), knees (curved arrow), and distal tibiae. The distribution of bone marrow activity depends on patient age. Younger children have relatively more metabolically active marrow than older children. Normal marrow activity is generally equal to or less than the liver. B,C: Axial PETCT images localize the forearm activity to the forearm muscles (arrows). Such activity can be seen in tense patients or may be related to physical activity.

injection of FDG (Fig. 29.21) (15). When FDG muscle activity is not bilaterally symmetric, the correlative anatomic information provided by CT is extremely useful in elucidating the underlying cause of the abnormality particularly when an intra- or perimuscular mass is present. Interpretation of the PET appearance of normal bone marrow in children requires knowledge of the age-dependent conversion patterns from hematopoietic to fatty marrow (21–24). Younger children have relatively more metabolically active and FDG-avid hematopoietic marrow within long bones than older children whose marrow has undergone fatty conversion. Intense FDG activity may be present in the physes of growing children (Fig. 29.20). Fluorodeoxyglucose uptake in normal bone marrow is generally less than or equal to that of the liver (Fig. 29.20). Diffuse and symmetric increased FDG bone marrow activity is often seen in patients receiving granulocyte colony-stimulating factor (G-CSF) (Fig. 29.22) (25). Occasionally, focal areas of increased FDG activity are present within the vertebral bodies that can be difficult to

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Figure 29.22. An 18-year-old woman under treatment for rhabdomyosarcoma who had recently received granulocyte colony-stimulating factor (GCSF). MIP anterior image shows marrow activity that is diffusely increased relative to the liver. This pattern of marrow activity is commonly seen in patients receiving G-CSF.

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Figure 29.23. This example illustrates the value of correlative PET-CT imaging in determining the cause of abnormal activity in the spine in this 19-year-old man with previously treated osteosarcoma. A,B: Axial PET-CT images localize a focus of abnormal activity to the spinous process of a thoracic vertebra (arrow). Utilizing a bone window, the CT image demonstrates a lucent line (arrowhead). This patient was involved in a motor vehicle accident several months before this scan, with injury to this area, although no fracture was diagnosed at that time. This activity resolved on subsequent PET-CT imaging and was felt to be due to fracture.

distinguish from a pathologic process. Generally, a repeating pattern of patchy increased activity throughout the spine can be seen on the sagittal or coronal images that is characteristic of physiologic uptake. When increased bone marrow activity is solitary or nonuniformly distributed, other causes, such as infection, metastatic disease, or primary bone malignancies, should be considered. Correlative CT imaging, utilizing a bone window, may reveal an underlying destructive process, fracture, or other pathology (Fig. 29.23).

References 1. Kluetz PG, Meltzer CC, Villemagne VL, et al. Combined PET/CT imaging in oncology. Impact on patient management. Clin Positron Imaging 2000;3: 223–230. 2. Eubank WB, Mankoff DA, Schmiedl UP, et al. Imaging of oncologic patients: benefit of combined CT and FDG PET in the diagnosis of malignancy. AJR 1998;171:1103–1110. 3. Charron M, Beyer T, Bohnen NN, et al. Image analysis in patients with cancer studied with a combined PET and CT scanner. Clin Nucl Med 2000; 25:905–910. 4. Bar-Shalom R, Yefremov N, Guralnik L, et al. Clinical performance of PET/CT in evaluation of cancer: additional value for diagnostic imaging and patient management. J Nucl Med 2003;44:1200–1209. 5. Townsend DW, Beyer T. A combined PET/CT scanner: the path to true image fusion. Br J Radiol 2002;75(Spec No.):S24–S30. 6. Stahl A, Dzewas B, Schwaiger M, et al. Excretion of FDG into saliva and its significance for PET imaging. Nuklearmedizin 2002;41:214–216. 7. Goerres GW, Von Schulthess GK, Hany TF. Positron emission tomography and PET CT of the head and neck: FDG uptake in normal anatomy, in

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benign lesions, and in changes resulting from treatment. AJR 2002;179: 1337–1343. Kostakoglu L, Hardoff R, Mirtcheva R, et al. PET-CT fusion imaging in differentiating physiologic from pathologic FDG uptake. Radiographics 2004;24:1411–1431. Zhu Z, Chou C, Yen TC, et al. Elevated F-18 FDG uptake in laryngeal muscles mimicking thyroid cancer metastases. Clin Nucl Med 2001;26: 689–691. Himms-Hagen J. Brown adipose tissue thermogenesis: interdisciplinary studies. FASEB J 1990;4:2890–2898. Hany TF, Gharehpapagh E, Kamel EM, et al. Brown adipose tissue: a factor to consider in symmetrical tracer uptake in the neck and upper chest region. Eur J Nucl Med Mol Imaging 2002;29:1393–1398. Cohade C, Osman M, Pannu HK, et al. Uptake in supraclavicular area fat (“USA-Fat”): description on 18F-FDG PET/CT. J Nucl Med 2003;44: 170–176. Hedlund GL, Kirks DR. Respiratory system. In: Kirks DR, ed. Practical Pediatric Imaging, 2nd ed. Cincinnati: Little, Brown, 1991:517–707. Gordon BA, Flanagan FL, Dehdashti F. Whole-body positron emission tomography: normal variations, pitfalls, and technical considerations. AJR 1997;169:1675–1680. Shreve PD, Anzai Y, Wahl RL. Pitfalls in oncologic diagnosis with FDG PET imaging: physiologic and benign variants. Radiographics 1999;19:61–77. Kostakoglu L, Wong JC, Barrington SF, et al. Speech-related visualization of laryngeal muscles with fluorine-18-FDG. J Nucl Med 1996;37:1771–1773. Tatlidil R, Jadvar H, Bading JR, et al. Incidental colonic fluorodeoxyglucose uptake: correlation with colonoscopic and histopathologic findings. Radiology 2002;224:783–787. Chander S, Meltzer CC, McCook BM. Physiologic uterine uptake of FDG during menstruation demonstrated with serial combined positron emission tomography and computed tomography. Clin Nucl Med 2002; 27:22–24. Barrington SF, Maisey MN. Skeletal muscle uptake of fluorine-18-FDG: effect of oral diazepam. J Nucl Med 1996;37:1127–1129. Mossberg KA, Mommessin JI, Taegtmeyer H. Skeletal muscle glucose uptake during short-term contractile activity in vivo: effect of prior contractions. Metabolism 1993;42:1609–1616. Daldrup-Link HE, Franzius C, Link TM, et al. Whole-body MR imaging for detection of bone metastases in children and young adults: comparison with skeletal scintigraphy and FDG PET. AJR 2001;177:229–236. Babyn PS, Ranson M, McCarville ME. Normal bone marrow. In: Mirowitz SA, Jaramillo D, eds. MRI Clinics. Philadelphia: WB Saunders, 1998: 473–495. Moore SG, Dawson KL. Red and yellow marrow in the femur: age-related changes in appearance at MR imaging. Radiology 1990;175:219–223. Ricci C, Cova M, Kang YS, et al. Normal age-related patterns of cellular and fatty bone marrow distribution in the axial skeleton: MR imaging study. Radiology 1990;177:83–88. Sugawara Y, Fisher SJ, Zasadny KR, et al. Preclinical and clinical studies of bone marrow uptake of fluorine-1-fluorodeoxyglucose with or without granulocyte colony-stimulating factor during chemotherapy. J Clin Oncol 1998;16:173–180.

30 Common Artifacts on PET Imaging Peeyush Bhargava and Martin Charron

Whole-body positron emission tomography (PET) with fluorodeoxyglucose (FDG) is fast becoming the standard of care in management of a variety of malignant and nonmalignant conditions. Two excellent reviews by Rohren et al. (1) and Kostakoglu et al. (2) describe the clinical applications of PET in oncology in adult patients. As more experience is gained in the pediatric population, indications for pediatric FDG-PET imaging are emerging (3–5). As with any other nuclear imaging modality, it is very important to recognize artifacts while reading the whole-body FDG-PET images for the subsequent correct management of patients. Recognition of artifacts improves the sensitivity and specificity of the study tremendously and reduces the need for further evaluation with other radiologic tests. This chapter discusses the normal biodistribution of FDG in pediatric patients, common artifacts seen on whole-body FDG-PET images, common causes of false-positive and false-negative findings, and recognition of artifacts.

Scanning Protocol Performing FDG-PET studies on pediatric patients presents a special challenge. The issues that require consideration specifically in the pediatric population include intravenous access, sedation, fasting, consent, and urinary tract activity. These technical issues specific to pediatric PET imaging have been dealt with in recent articles (6–8). Procedure guidelines and patient preparation techniques for the adult FDG-PET imaging have been published in the literature (9–11). Institutions performing PET studies on pediatric patients are recommended to consult these reports and to develop their own protocols. Essentially, patient preparation is the same for pediatric patients as for adults. Typically after an overnight fast (or fasting for 6 to 8 hours), fluorine-18 (18F)-FDG is injected intravenously, and after waiting for an uptake period of around an hour (with minimal physical activity), multiple bed positions emissions scans are acquired on a dedicated 543

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whole-body scanner from the base of skull to the level of thighs. The blood glucose level is usually checked by finger-stick method at the time of radiotracer injection. Paying careful attention to injection and scanning protocol is very important in acquiring and interpreting good-quality images and avoiding artifacts. Images are reconstructed using an iterative reconstruction algorithm, and attenuation correction is applied. When using a PET–computed tomography (CT) scanner, CT data can be used for attenuation correction and the scan can be acquired in a shorter period of time. Getting a good history from the patient or parents and making sure that recent CT or magnetic resonance imaging (MRI) films are available for correlation at the time of reading PET studies is a prerequisite for avoiding common pitfalls.

Reviewing PET Studies Positron emission tomography images are always reviewed on a computer monitor. This provides the ease of toggling between the different set of images and different cross sections and changing the intensity. Raw projection image (or the rotating image) can also be reviewed. We strongly discourage reading PET images from films and recommend review of cross-sectional images in gray scale. After some experience, readers develop their own style of reviewing images. In our default display, the rotating attenuation corrected image is seen on the left side of the window, and different cross sections (coronal, transaxial, and sagittal) are on the right. We review the coronal images first (from anterior to posterior), then confirm our findings on other cross sections, and, if needed, review the non–attenuation-corrected images. The non–attenuation-corrected images show intense uptake in the superficial structures and photopenia in the region of deeper structures. They can be differentiated from attenuation-corrected images by intense uptake in skin and in the superficial aspect of the right lobe of liver and by scattered activity in the lungs (Fig. 30.1). The reconstructed transmission image may also be used on occasion as a guide to anatomy. We feel that anatomy of FDG distribution is best appreciated in coronal views, but we have noticed that radiology residents and radiologists prefer looking at transaxial images. It is very important to know the transaxial and sagittal anatomy also, especially for direct comparison of PET images to CT or MRI films. It is also good to know all available options for image manipulation. For example, in one option, a mouse click over any lesion seen on one cross-sectional slice brings up the corresponding slice on other cross-sectional images. Images are always read with attention to patient preparation, scanning protocol, indication, and detailed patient history and are compared to recent CT and MRI images, whenever available. Asymmetric uptake should be viewed with suspicion, especially in the head and neck region. Active neoplastic lesions or malignant lesions are usually seen as foci of intense FDG activity (or abnormal focal hypermetabolism). The standard uptake value (SUV) of lesions should be measured and reported. An SUV value of more than 2.5 is

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B Figure 30.1. Coronal non–attenuation-corrected image (A), reconstructed transmission image (B), and attenuation-corrected image (C) from a wholebody positron emission tomography (PET) scan. (Continued)

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C Figure 30.1. Continued.

likely to be consistent with malignancy. When evaluating lung nodules, activity is compared with mediastinal blood pool uptake and more active lesions are considered likely to be malignant. If adrenal nodules are more active than liver uptake, they are considered likely to be malignant.

Normal Distribution of FDG in Pediatric Patients To recognize what is abnormal on PET images, it is very important to know the normal biodistribution of FDG and normal variants. Various articles have described in detail the normal distribution of FDG in adults and the artifacts and pitfalls that can be encountered while reading whole-body FDG-PET images (12–16). The normal distribution of FDG does not differ significantly between adult and pediatric patients. Some of the important differences seen on pediatric images are moderate to intense and symmetric uptake in the epiphysis of long bones, mild to moderate activity in the thymus (seen as an inverted Vshaped structure in anterior mediastinum; Fig. 30.2), and changes in glucose metabolism in the brain in neonates. After the age of 1 year, cerebral glucose metabolism is similar to that in adults. Otherwise, the biodistribution of FDG is similar in pediatric patients and adults, with intense activity seen in the cortex, basal ganglia, and cerebellum. White matter and ventricles are usually seen as photopenic defects. Extraocular muscle activity is generally seen as

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Figure 30.2. Characteristic inverted V-shaped uptake in thymus.

small foci of moderate to intense activity in orbital region. Mild to moderate activity can be seen in the spinal cord, especially proximally. Mild to moderate, variable, and symmetric activity is seen in the oropharynx, tonsils, and salivary glands. Moderate to intense activity is seen in the vocal cords (usually as an inverted U-shaped structure), especially if the patient is talking during the uptake period (Fig. 30.3). Variable uptake can be seen in skeletal muscles depending on physical activity. Muscular uptake is usually mild to moderate in intensity, linear, and symmetric. Thyroid, airways, and esophagus are normally not seen on PET images. Diffuse uptake in thyroid could be from thyroiditis or Graves’ disease (Fig. 30.4). Focal uptake in the thyroid should be viewed with suspicion and evaluated further. Physiologic uptake in brown fat can be seen in the neck, supraclavicular regions, axilla, mediastinum, and posterior intercostal regions as foci of

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Figure 30.3. Physiologic uptake in vocal cords.

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Figure 30.4. Diffused intense uptake in both lobes of thyroid, secondary to thyroiditis. A malignant lung nodule is seen in the right upper lobe.

moderate to intense uptake that are symmetric (Fig. 30.5). This finding was initially thought to be muscle uptake but is now believed to be related to thermoregulation. Lungs, cortices of long bones, and usually muscles also are seen as photopenic areas. Mild mediastinal blood pool activity is usually seen as focal lesions in the lungs and hilum; those more intense than the mediastinal blood pool activity are considered suspect for neoplastic involvement. Walls of large vessels may be seen from inflammation in the atherosclerotic plaques. The diaphragm and intercostal and accessory muscles may be visualized in patients with respiratory distress (Fig. 30.6). Variable degree of uptake can be seen in myocardium depending on patient preparation, insulin, and blood glucose levels. Administration of insulin (or a recent meal) forces FDG (and glucose) to be taken up by myocardium, muscle, and fatty tissue. This is helpful in cardiac imaging. Minimal or no myocardial uptake is usually recommended for oncologic imaging, especially for evaluation of hilar nodes. Moderate and sometimes heterogeneous activity is seen in the liver. Normally, the spleen is smaller than the liver and less intense in uptake. A

Figure 30.5. A: Projection image of a patient with lymphoma showing symmetric foci in the supraclavicular region. Computed tomography (CT) correlation with transaxial image (B) shows uptake in a region of fat density (C).

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variable degree of uptake is seen in bowel. Usually the stomach wall and colonic activity is prominent. This physiologic uptake could be intense, but it is generally linear and diffuse. Focal uptake should be evaluated further by colonoscopy. Mild physiologic uptake in bone marrow leads to faint visualization of vertebral bodies, the pelvis, and the proximal ends of humerus and

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femur. Increased uptake in bone marrow can be seen in anemia, rebound from chemotherapy, or from pharmacologic stimulation (therapy with colony-stimulating factors) (Fig. 30.7). Because FDG is excreted by the kidneys, mild to moderate activity is seen in the cortex, and intense activity can be seen in the pelvis, ureters, and urinary bladder. Focal stasis in the ureter and activity in bladder diverticulum can be confused with hypermetabolic adenopathy. A history should be obtained about any surgeries, such as renal transplant and diversion procedures. Reproductive structures in the pelvis are usually not visualized, but physiologic activity is frequently seen in the uterus as a focus superior to the bladder (Fig. 30.8). Mild to moderate and usually symmetric activity is seen in the testes. Fatty tissue is usually seen as photopenic areas in the subcutaneous region and in the abdomen. Various interventions have been reported to reduce or eliminate some of these artifactual foci of FDG activity. Bowel cleansing or motility inhibitors can reduce activity in bowel loops. Diuretics and catheterization can wash out activity in the urinary tract. Oral diazepam has

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Figure 30.7. Upper row images (pretherapy scan) show uptake in tonsillar lymphoma and injection artifact at the level of the left wrist. Lower row images (posttherapy scan) show intense bone marrow and spleen activity secondary to chemotherapy.

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B Figure 30.8. A: PET image showing a focus of intense uptake superior to the urinary bladder that corresponds to the uterus (menstruating) on CT scan image (B).

been shown to reduce muscle and fat uptake. We have found that these interventions require a lot of effort, interfere with day-to-day work flow, and do not provide much additional gain in clinical information. In the pediatric population, however, sedation and bladder catheterization may sometimes be required for patient immobilization and reduced risk of contamination.

Artifacts Related to Image Acquisition and Reconstruction Whenever possible, whole-body images should be acquired with the patient’s arms up. In patients with head and neck pathology, a second bed position should be acquired of the head and neck, with the arms

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down. When chest images are acquired with the arms down, focal skinfold uptake in axilla can mimic hypermetabolic nodes. It is important that the patient stays still during the entire scan, as patient motion can give rise to artifacts (Fig. 30.9). These can be confirmed on non–attenuation-corrected images. If required, patients can be sedated by using IV medication or even general anesthesia. Care should be taken during injection of FDG to avoid any tissue infiltration and to make sure that the injection is given in the arm opposite to the affected side. Dose infiltration is usually seen as a large focus of intense activity with surrounding streak photopenia (Fig. 30.7). Nodal uptake from infiltrated dose can be mistaken for neoplastic involvement. Dose infiltration also interferes with calculation of SUV value. Positron emission tomography images are reconstructed using iterative reconstruction algorithms as opposed to filtered back-projection. Even with iterative reconstruction algorithms, photopenic areas are seen around the foci of intense uptake, such as the urinary bladder, or dose infiltration. This may interfere with evaluation of the pelvis. Attenuation correction can also create artifacts, especially in very obese patients and in using CT data for attenuation correction, especially

Figure 30.9. Coronal image at level of myocardium showing focal uptake in left perihilar region, an artifact from patient motion.

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when using IV and oral contrasts. These can be avoided by the review of non–attenuation-corrected images.

Iatrogenic Artifacts Oncologic patients presenting for PET imaging have elaborate histories complicated by medical and surgical procedures, which can alter the distribution of FDG (17). A careful history should be taken about various medical and surgical procedures, chemotherapy, and radiation therapy, with their respective dates. Information should be taken about the insertion of IV catheters (Fig. 30.10), ports (Fig. 30.11), tubes, and

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ileostomies (Fig. 30.12). Inflammatory uptake may be seen in superficial surgical wounds for 4 to 6 weeks. Sites of surgery and biopsies usually fill with serous hypometabolic fluid in the next few days and may be seen on PET scan as ring-shaped foci, with surrounding inflammation (Fig. 30.13). False-positive findings can be seen from inflammation secondary to radiation. Postradiation changes can persist for 4 to 6 months. Radiation to marrow causes replacement with fatty tissue, which is seen on PET as

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Figure 30.12. PET images showing focal uptake in the right lower quadrant of the abdomen from an ileostomy.

a photopenic area (Fig. 30.14). Radiation-induced pneumonitis, esophagitis, myositis, or vasculitis can also be visualized on PET (18). Radiation-induced changes can be recognized by the geographic pattern of lesions, in the shape of a radiation port (Fig. 30.15). Chemotherapy is also known to change the biodistribution of FDG. The reason for this is not entirely known, but posttherapy images frequently show increased uptake in the myocardium, small and large bowel loops, and, to some extent, the liver and spleen. Rebound bone marrow activity is seen as diffuse and moderate to intense uptake. This can be difficult to distinguish from bone metastasis. CORONAL

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Figure 30.13. Two, small, ring-shaped foci seen in the region of the right breast in a patient who recently had biopsy of tumor and resection of axillary lymph node.

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Figure 30.14. PET images of a patient with a history of radiation to the abdomen, showing a photopenic defect in the region of lumbar vertebral bodies.

A prosthesis of any kind, if large enough, is generally seen as a photopenic defect on PET imaging. If the prosthesis is recently placed, inflammatory uptake can be seen around it, which may last for 4 to 6 weeks. Nonspecific activity is known to persist around a hip prosthesis for years (Fig. 30.16). Increased uptake in the thymus can be seen secondary to chemotherapy, stem cell transplantation, radiotherapy, or iodine-131 therapies. Acute changes in blood glucose levels can also affect the distribution of FDG. The administration of insulin or glucose or a recent meal can

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Figure 30.15. PET images of a patient with a history of radiation to metastatic lesion in the left femur. Increased uptake in pattern of geographic radiation port is suggestive of myositis and vasculitis.

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Figure 30.16. Coronal image of a patient showing nonspecific activity around hip prostheses.

cause increased uptake in skeletal muscles, myocardium, and fatty tissue. Acute intravascular thrombosis elicits an inflammatory response that can be seen as a focus of increased FDG activity. As the thrombus becomes chronic and gets replaced by scar tissue, the focus becomes photopenic (Fig. 30.17). Catheter-related focal FDG activity can be from intravascular thrombosis or infection (Fig. 30.18) (19).

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Figure 30.17. A: Transaxial chest image showing a ring-shaped photopenic defect in the anterior mediastinum that corresponds to a chronic thrombus post-repair of an ascending aortic aneurysm (B).

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Common Causes of False-Positive Findings Fluorodeoxyglucose as a tracer is not specific to tumors or malignancies; increased FDG activity can also be seen in inflammatory and infectious lesions. Inflammatory cells also show increased glucose metabolism. False-positive findings from these foci of inflammation or infection are an important cause of low specificity of PET studies (Fig. 30.19) (20). Dual time point imaging has been advocated to recognize these false-positive findings with some success. This technique is useful in the evaluation of solitary pulmonary nodules. It has been shown that FDG uptake in neoplastic lesion increases over a period of

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B Figure 30.19. A: PET images of a patient with lung nodule showing focal hypermetabolism in peripheral lower left lateral lung/chest wall that corresponds to a healing rib fracture on CT scan (B).

time and that of benign lesion decreases. Therefore, a second acquisition 2 hours after FDG injection may be helpful in differentiating the two. Benign tumors and second primaries are also an important cause of false-positive or incidental findings on PET scans (21). These should be pursued further by obtaining a more complete history from the patient or referring physician, comparing PET images to other radiologic imaging, and by evaluating further. An exhaustive list of benign causes of FDG uptake on whole-body FDG imaging can be found in the article by Bakheet and Powe (22).

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Common Causes of False-Negative Findings Fluorodeoxyglucose-PET is known to be limited in evaluation of low-grade malignancies such as low-grade lymphomas, bronchoalveolar cancers, and carcinoids. Micrometastases in lymph nodes are usually missed on PET scans. Also, with PET imaging, confident evaluation is not possible of lesions smaller than 1 cm in size on anatomic imaging. Hyperglycemia (by competition between blood glucose and the injected FDG) is also known to be a cause of false-negative PET findings.

Common Causes of Photopenic Defects Frequently, photopenic foci or larger areas are seen on PET images. These can result from hypometabolic structures (white matter and ventricles, fatty tissue, resting skeletal muscle, cortical bone), benign cavities (stomach, bowel, lungs, gall bladder), benign effusions (pleural and pericardial effusions, ascites, hydrocele), postsurgical collections (hematoma, seroma), benign cysts (renal, hepatic cysts), prostheses (breast, hip, and knee prostheses, chemotherapy ports), malignant collections (tumor necrosis), acquisition artifacts (around kidneys and bladder activity), posttherapy changes (scar tissue post–chemo/radiation and bone marrow replacement after radiation), or other causes (chronic thrombi, crossed cerebellar diaschisis, or calcified uterine fibroids). It is important to recognize these artifacts and to correlate them with anatomic imaging. Large tumors frequently show central necrosis that is seen on PET imaging as a photopenic defect, with the lesion itself seen as a ring-shaped focus with hypermetabolic margins. The gallbladder may be seen as a photopenic defect, and inflammation of its walls may cause increased FDG uptake (Fig. 30.20).

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Figure 30.20. PET images of a patient with chronic cholecystitis showing a photopenic defect in the region of the gallbladder and increased uptake in the gallbladder wall.

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PET-CT Artifacts The new imaging technology of acquiring PET and CT images in one machine at the same time, using CT data for attenuation correction, has many advantages but also has its share of artifacts and pitfalls (23–25). These artifacts can be divided into three groups: attenuation-correction artifacts, motion artifacts, and CT truncation artifacts. Because of differences in energy and the way photons are attenuated by the body tissues, when CT transmission data are used for attenuation correction, FDG–avid false-positive findings are seen in the region of metallic implants, IV and oral contrast media, and other radiodense areas. These false-positive findings can be recognized by reviewing the non–attenuation-corrected images and by the presence of beam-hardening artifact on CT images. They can be avoided by not using IV contrast, by using water-based oral contrast, or by using a low-dose CT for attenuation correction and acquiring a separate contrast-enhanced diagnostic CT scan. Motion artifact may result when there is patient or organ motion between the PET scan and the CT scan. This can cause misregistration in the regions of the diaphragm, head and neck, and extremities. Some of this can be avoided by having patients hold their breath at the end of normal expiration during CT scanning, breathe normally during PET acquisition, and lying still during the scan. Computed tomography truncation artifacts can be avoided by having the patient place both arms up during PET and CT acquisition.

Recognizing Artifacts It is impossible to list all possible false-positive and false-negative findings that can be seen on PET images. Experience is the best way to recognize pitfalls and artifacts while reading these studies. The artifacts discussed in this chapter are from the authors’ experience of reading PET studies predominantly in adult patients, but they give a comprehensive idea of possible artifacts and their patterns that may be seen on pediatric PET images. Every reader should develop a consistent way of reviewing images and should correlate images with a thorough and careful history and findings on other imaging tests. One should know as much as possible about the patient. The reader should be conversant in cross-sectional anatomy and should be able to compare PET images directly to CT or MRI images whenever available. He or she should be well versed in normal distribution and normal variants of FDG uptake. Information about patient preparation, the imaging protocol, the patient’s blood sugar level, and the site of the intravenous injection should be available at the time of review of these images. Positron emission tomography–CT has been proposed as a way to avoid some of these artifacts and pitfalls. Recognizing these artifacts increases the sensitivity and specificity of a scan, reduces the number of equivocal findings, and prevents unnecessary additional workup.

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Chapter 30 Common Artifacts on PET Imaging 22. Bakheet SM, Powe J. Benign causes of 18-FDG uptake on whole body imaging. Semin Nucl Med 1998;28(4):352–358. 23. Kostakoglu L, Hardoff R, Mirtcheva R, et al. PET-CT fusion imaging in differentiating physiologic from pathologic FDG uptake. Radiographics 2004;24(5):1411–1431. 24. Kapoor V, McCook BM, Torok FS. An introduction to PET-CT imaging. Radiographics 2004;24(2):523–543. 25. Schoder H, Erdi YE, Larson SM, et al. PET/CT: a new imaging technology in nuclear medicine. Eur J Nucl Med Mol Imaging 2003;30(10):1419–1437.

Index

A AADC. See Aromatic amino acid decarboxylase AAP. See American Academy of Pediatrics Absorbed dose absorbed fraction of, 40–41 cumulated radioactivity of, 38–39 equilibrium absorbed dose constant of, 39–40 of F-FDG, 44 of O-labeled water, 45–46 specific absorbed dose fraction of, 41–43 of thymidine, 45 total energy absorbed by target organ with, 40 Absorbed fraction, 40–41 Acetylcholine, 394 Acquired immunodeficiency syndrome (AIDS), 448, 450–451 ACR. See American College of Radiology Actinomyces naeslundii, 455 Acute insulin responses (AIRs), 481 Adaptive responses, 62 Adenomas, 466 Adenosine triphosphate (ATP), 226, 479, 530 ADHD. See Attention-deficit/ hyperactivity disorder Adipose tissue, 223–226 Adrenal medulla, 249

AIDS. See Acquired immunodeficiency syndrome AIRs. See Acute insulin responses AJCC. See American Joint Committee on Cancer ALCAPA. See Anomalous origin of the left coronary artery arising from the pulmonary artery Algorithms, 487 analytical reconstruction, 159–162 attenuation weighted ordered subset expectation maximization iterative, 474 iterative reconstruction, 162–165, 553 Monte Carlo, 109 row action maximum likelihood, 113 «-amino-3-hydroxy-5-methyl-4isoxazolepropionate (AMPA), 331 Alzheimer’s disease, 393 American Academy of Pediatrics (AAP), 21, 129 American College of Radiology (ACR), 21 American Joint Committee on Cancer (AJCC), 304 American Society of Anesthesia (ASA), 21

American Society of Anesthesiologists, 129 American Society of Radiologic Technologists (ASRT), 132 Amine precursor uptake and decarboxylation (APUD), 473, 482 Amino acid agents, 201–203 Amino acid PET, 182–184, 326–327 biopsy guidance with, 191–192 grading of, 185–186 prognosis with, 188 recurrence v. radiation necrosis, 197–198 treatment response with, 194 AMPA. See «-amino-3-hydroxy5-methyl-4isoxazolepropionate Amphetamine (AMPH), 338 Amphetamine-induced dopamine, 397 Anaerobic glycolysis, 530 Analytical reconstruction algorithm, 159–162 backprojection filtering, 159–160 FBP, 160–162 Anaplasia, 256–257 Aneurysms, 419–420, 558 Anger logic, 104 Anger position logic, 143 Angiogenesis, 207 Angiography, 420 Annihilation photons, 96, 105 565

566

Index

Anomalous origin of the left coronary artery arising from the pulmonary artery (ALCAPA), 417–419 Anxiety, 349–350 Anxiolytic drugs, 127 Aortic aneurysm, 558 Apotosis, 208 APUD. See Amine precursor uptake and decarboxylation Aromatic amino acid decarboxylase (AADC), 473 Arterial input function, 395 Arterial switch operation (ASO), 416 ASA. See American Society of Anesthesia ASL. See Arterial spine labeling ASO. See Arterial switch operation Asperger’s syndrome, 348 Aspergillosis, 507 ASRT. See American Society of Radiologic Technologists Astrocytoma, 180 Ataxia-telangiectasia, 534 Atherosclerosis, 420 ATP. See Adenosine triphosphate Attention-deficit/hyperactivity disorder (ADHD), 72, 389, 505. See also Obsessive-Compulsive Disorder (OCD) background of, 334–336 children and, 72, 75 11 C-altropane and, 391 male dominance of, 78 medications for, 338–340 PET/SPECT imaging for, 336–338 PET/SPECT medications for, 338–340 symptoms of, 334 Attenuation correction, 97, 107–108, 152–154 Attenuation weighted ordered subset expectation maximization iterative algorithm, 474

Autism, 505 background of, 349 brain activity and, 347–349 PET/SPECT imaging in, 346–349 reversed hemispheric dominance from, 348 serotonin abnormalities in, 348 B Background radiation, 31 Backprojection filtering, 159–160 BAT. See Brown adipose tissue BCNU. See Bischloroethylnitrosourea Benzodiazepine binding, 350 Bilateral Wilms’ tumor, 260–262 Biopsy error, 281–282 FDG-PET scan and, 434–435 guidance with FDG-PET scan, 189–192 methionine guidance for, 192 nondiagnostic, 269 primary bone tumors and, 281–282 stereotactic, 183, 197 Bischloroethylnitrosourea (BCNU), 195 Blood flow cerebral, 324 myocardial, 407–410 pulmonary, 418 Blood glucose levels, 548 Bone allografts, 273 Bone scintigraphy, 231–230 Bone tumors, 510–512 BPCA. See Best Pharmaceuticals for Children Act Brain, development of, 323–331 Brain imaging, 116, 329–330 Brain imaging studies, 323–327 anatomic studies of normal, 323 radiopharmaceutical-based, 324–327 fluorodeoxyglucose studies, 325–326 labeled amino acid PET, 326–327

PET radiation exposure, 327 PET studies of brain development, 325 SPECT studies of, 324 Brain metastases, 198 Brain tumors, 175–209 biopsy guidance with, 189–192 CT diagnosis of, 175 detection of, 176–184 FDG uptake analyzed in, 177–178 future studies for, 206–209 PET for evaluation of drug kinetics, 208–209 PET for receptor imaging, 206 PET imaging for assessment of gene therapy protocols, 207–208 PET imaging of angiogenesis, 207 PET imaging of apotosis, 208 grading of, 183–186 MRI diagnosis of, 175 other agents and, 201–206 amino acid agents with longer half life, 201–203 DNA synthesis agents, 203–205 hypoxia agents, 206 membrane biosynthesis agents, 205 prognosis of, 186–189 recurrence v. radiation necrosis, 195–198 status postradiation, 176 treatment planning for, 198–201 treatment response of, 192–195 Brown adipose tissue (BAT), 223–226 Brown fat, 127 C CAD. See Coronary artery disease Carbon-11 hydroxyephedrine (HED), 249, 250, 314

Index Carbon-11-based tracers, 295–296 Carbon-11-labeled methionine (C-Met), 295–296 Carcinoma, 436 Cardiac imaging, 409 Cardiac PET protocols, 415 Cardiomyopathies of diverse origin, 422–423 Cardiovascular applications, 407–423 clinical applications of, 415–423 ALCAPA, 417–419 cardiac transplant vasculopathy, 421–422 cardiomyopathies of diverse origin, 422–423 Kawasaki disease, 419–421 transposition of great arteries, 416–417 principles of emission tomography applied to, 408–415 cardiac PET protocols, 415 fatty acids, 410–412 glucose metabolism, 412 MBF evaluation, 408–410 oxygen, 410–412 PET data, 412–414 radiopharmaceuticals, 408 CAT. See Computed axial tomography Catecholamine, 249–253 Catecholamine-like tracers, 249–253 CF. See Cystic fibrosis C-flumanzenil (FMZ), 392–393 Chemotherapy, 228, 271, 273 port, 555 Children, 5. See also Pediatric patient direct benefit of PET research for, 65 fasting for successful sedation of, 22 injection sites for, 5 nuclear imaging technologist and, 5–6 parental permission for research with, 65–66 patient preparation for, 125–126 PET ethics for, 72–87

PET regulations for, 47–57 PET research protection for, 53 PET-CT for, 121–133 physical considerations for, with imaging, 116–117 physical differences from adults of, 74 procedural sedation for PET scans with, 66 scanning of, 128–132 sedation issues with, 21–28 sensitivity to radiation of, 30 Children’s Oncology Group (COG), 222 Chronic granulomatous disease (CGD), 454–456 Chronic osteomyelitis, 268 Clear cell sarcoma, 257 C-Met. See Carbon-11-labeled methionine CMV. See Cytomegalovirus CNS. See Central nervous system Cocaine, 391–392 COG. See Children’s Oncology Group Coincidence electronics, 140–141 Coincidence imaging, 135–165 coincidence detection using GCPET, 137–154 acquisition geometry, 139–140 attenuation correction, 152–154 coincidence electronics, 140–141 count rate, 141–144 crystal properties, 137–138 dual-energy window technique, 146–148 geometric sensitivity, 148–152 spatial resolution, 144–146 commercial GCPET systems for, 165 image reconstruction analytical reconstruction algorithm, 159–162 data rebinning, 154–156 imaging geometry, 156–159 iterative reconstruction algorithm, 162–164

567

image reconstruction of, 154–164 SPECT, 135–137 Coincidences, 141 random, 97 scattered, 141 single, 141 true, 141 Congenital hyperinsulinism, 479 Conjuctivitis, 452 Conscious sedation, 24 Coronary artery disease (CAD), 407 Cortical stimulation, 496 Corticosteroids, 507 Cotswolds Classification, 220 Crohn’s disease, 437, 463 Cryptococcus neoformans, 450 CT. See Computed tomography Current research efforts, 502–511 cardiology, 506 inflammatory disease, 506–507 neurology, 503–506 oncology, 508–513 bone tumors, 510–512 central nervous system tumors, 508–509 hepatoblastoma, 512–513 leukemia, 509–510 lymphoma, 509–510 neuroblastoma, 510 pheochromocytoma, 512 potential causes of misinterpretation of FDG-PET, 508 Wilms’ tumor, 510 Cushing’s syndrome, 315 Cystic fibrosis (CF), 507 Cystic ovary, 490 Cytomegalovirus (CMV), 429 D DAT. See Dopamine transporter Data acquisition, 106–107, 474 Data analysis, 474–476 Data processing, 474 Data rebinning, 154–156 Data safety monitoring board (DMSB), 51 Dead time, 109–111 Decay correction, 109–111

568

Index

Deep sedation, 24 definition of, 25 requirements for safe, 25 Desmoid tumor, 296 Developing brain, 323–331 brain imaging studies, radiopharmaceuticalbased studies, 324–327 correlation of SPECT with other modalities and, 327–329 imaging studies of, 323–327 anatomic studies of normal, 323 pediatric PET-CT brain imaging, 329–330 DFOV. See Display field of view DHHS. See Department of Health and Human Services Diabetes, 473 Diazepam, 538 Diffuse bone marrow uptake, 226–229 Disease(s) Alzheimer’s, 393 cerebral inflammatory, 505 chronic granulomatous, 454–456 coronary artery, 407 Crohn’s, 437, 463 Hodgkin’s, 220–221 inflammatory, 506–507 inflammatory bowel, 452–454, 461–468 Kawasaki, 419–421, 451 Lesch-Nyhan, 391 metastatic, 283–286 micrometastatic, 271 Paget’s, 268 Parkinson’s, 389, 390 pulmonary, 283–284 splenic, 230 Wilson’s, 391 Diurectics, 551 DMSB. See Data safety monitoring board DNA synthesis agents, 203–205 DNET. See Dysembryoplastic neuroepithelial tumor Dopamine, 245, 387 amphetamine-induced, 397 epilepsy and, 504

neurotransmission, 388 striatal, 388 Dopamine transporter (DAT), 335, 389–392 Dopaminergic ligand, 387 Dopaminergic system, 387–392 Dose absorbed, 38–46 effective, 61 low, radiation, 84 medical internal radiation, 327 per cumulated activity, 41 shielded radiopharmaceutical syringe, 8 Dosimetry, 409 DSCE. See Dynamic susceptibility contrastenhanced Dual-energy window technique, 146–148 Dual-time point imaging, 303 Dual-window technique, 145 Duchenne dystrophy, 423 Dural metastasis, 178 Dynamic receptor imaging, 394–397 Dynamic susceptibility contrast-enhanced (DSCE), 329 Dysembryoplastic neuroepithelial tumor (DNET), 178, 180–181, 202 Dyskinetic myocardium, 413 Dyslexia background of, 343–345 genetics and, 344 PET/SPECT imaging in, 345–346 E Echocardiography, 419 ED. See Effective dose EEG. See Electroencephalogram Effective dose (ED), 61 EICESS. See European Intergroup Cooperative Ewing’s Sarcoma Study Elevated glucose metabolism, 183

EMLA. See Eutectic mixture of local anesthetics Encephalopathies, 325 Endocarditis, 438 EORTC. See European Organization for Research and Treatment of Cancer Epilepsy, 116, 361–381 dopamine and, 504 emerging clinical applications of neurochemical PET imaging and, 379–380 epileptogenic focus, 364 extratemporal, 369–376 FDG-PET imaging in extratemporal and, 369–376 FDG-PET studies in LennoxGastaut syndrome and, 378 FDG-PET studies of children with infantile spasms and, 377–378 ictal SPECT and, 364–366 imaging for presurgical workup and, 361–363 interictal and ictal PET studies, 378–379 interictal FDG and, 364–366 interictal FDG-PET studies in TLE, 366–369 neurology and, 504–505 PET for functional and neurochemical imaging and, 361 regional glucose hypometabolism and, 364 Equilibrium absorbed dose constant, 39–40 Erythrocyte sedimentation rate (ESR), 431 ES. See Ewing sarcoma ESR. See Erythrocyte sedimentation rate European Intergroup Cooperative Ewing’s Sarcoma Study (EICESS), 274 European Organization for Research and Treatment of Cancer (EORTC), 307

Index Eutectic mixture of local anesthetics (EMLA), 76–78 Ewing sarcoma (ES), 267, 272, 274–275, 312–313 Exact spatial correlation, 490 Extranodal staging, 230–234 Extrastriatal receptors, 397 Extratemporal epilepsy, 369–376 F F-« methyltyrosine, 293 Fat brown, 127 retroperitoneal brown, 532 supraclavicular brown, 531 Fatty acidS, metabolism, 410 Fatty acids, 410–412 FDA Modernization Act (FDAMA), 51 FDG. See F-fluorodeoxyglucose; Fluorine-18 fluorodeoxyglucose; Fluorodeoxyglucose FDG-PET scan advantages of, 434 biopsy and, 434–435 biopsy guidance with, 189–191 for children with infantile spasms, 377–378 clinical applications of, 448–456 considerations for accurate, 435–436 experience with, 437–440 false-positive/false-negative findings in, 493 FUO used with, 431–440 grading of, 183–185 imaging in extratemporal epilepsy and, 369–376 for Lennox-Gastaut syndrome, 378 lymphoma and, 222 mechanisms of FDG uptake by cells and, 431–432 misinterpretation of, 508 prognosis of, 186–189 rationale for use of, in FUO, 432–433 recurrence v. radiation necrosis and, 195–198

studies regarding, 436–437 in TLE, 366–369 treatment response and, 192–194 F-DOPA. See Fluorine-18 (18F)labeled L-fluoro-DOPA Fentanyl, 28 Fever of unkown origin (FUO), 428–441 common causes of, 433 definition and classification of, 428–429 general criteria of, 428 pediatric, 428–429 diagnosis of, 430–440 FDG-PET scan, 431–440 radiographic evaluation of children with, 431 radionuclide scans, 431 epidemiology/etiology, 429–430 possible causes of, 428 studies regarding, 436–437 F-fluorodeoxyglucose (FDG), 44, 51 Fibroma, 296 Fibrous dysplasia, 268, 280 FLT. See Fluorine-18 fluoro-3’deoxy-3’-Lfluorothymidine Fluorine, 291–293 Fluorine-18 fluoro-3’-deoxy-3’L-fluorothymidine (FLT), 293–295 Fluorine-18 fluorodeoxyglucose (FDG), 13 Fluorine-18 (18F)-labeled Lfluoro-DOPA (F-DOPA), 482–483 Fluorodeoxyglucose (FDG), 110, 325–326 administration of, 15 benign uptake of, 223 brain imaging studies, radiopharmaceuticalbased, 325–326 brown adipose tissue and skeletal muscle uptake of, 223–226 diffuse bone marrow uptake of, 226–229 normal distribution of, in pediatric patients, 546–552

569

osseous uptake of, 247 physiologic colonic activity, 461–462 projection images of, 247 thymus uptake of, 222–223 uptake of in, brain tumors, 177–178 uptake phase of, 16 whole body clinical scans of, 111 fMRI. See functional magnetic resonance imaging; functional MRI FMZ. See C-flumanzenil Frontal hypoperfusion, 347 Functional magnetic resonance imaging (fMRI), 73, 336 FUO. See Fever of unkown origin G Gadolinium-diethylenetriamine pentaacetic acid (Gd-DTPA), 486 Gamma camera-based positron emission tomography (GCPET), 135 attenuation correction, 152–154 coincidence detection by, 137–154, 140–141 commercial, systems, 165 dual-energy window technique and, 146–148 geometric sensitivity of, 148–152 nonuniform sensitivity of, 150 sensitivity profile of, 151 spatial resolution of, 144–146 Ganglioglioma, 180 Ganglioneuroblastoma, 251 Gastroenteropancreatic (GEP), 473 Gastrointestinal intestinal stromal tumors (GISTs), 305 GCPET. See Gamma camerabased positron emission tomography

570

Index

Gd-DTPA. See Gadoliniumdiethylenetriamine pentaacetic acid Gene therapy protocols, 207–208 General anesthesia, 24 definition of, 25 for scanning, 129–130 GEP. See Gastroenteropancreatic Germ cell tumor, 178, 261, 315–316 GISTs. See Gastrointestinal intestinal stromal tumors Gleevec, 305 Glucose levels, 14–15 GLUT. See Surface glucose transporter proteins Granulocyte colony-stimulating factor (G-CSF), 539–541 H HD. See Hodgkin’s disease HED. See Carbon-11 hydroxyephedrine Hepatoblastoma, 512–513 Hepatocellular carcinoma, 436 Hereditary spastic paraplegia (HSP), 506 HI. See Hyperinsulinism High-resolution spiral CT (HRCT), 283 Histiocytosis X, 316 Hodgkin’s disease (HD), 220–221, 437 Homovanillic acid (HVA), 74 Hormesis, 32 Human immunodeficiency virus (HIV), 433 Hyperfractionation, 198 Hyperinsulinism (HI) congenital, 479 focal, 479–481 gross and histopathologic section of, 480 of infancy, 472–476 localization of focal forms, 479–483 technique with, 474–476 localization of focal pancreatic lesions and, 481–483

interventional radiology and, 482 PET using F-DOPA, 482–483 pharmacologic tests, 481–482 pancreatectomy and, 481 Hypoglycemia, 472 Hypometabolism bilateral temporal, 369 cerebellar, 369 regional glucose, 364 Hypoxia agents, 206 I Iatrogenic artifacts, 554–558 IBD. See Inflammatory bowel disease I-benzamide (IBZM), 340 IBZM. See I-benzamide Ictal SPECT, 364–366 Ileaostomy, 556 Image acquisition, 552–554 Image reconstruction, 106–107, 154–164 analytical reconstruction algorithm, 159–162 artifacts related to, 552–554 data rebinning, 154–156 imaging geometry, 159–162 iterative reconstruction algorithm, 162–164 Image reconstruction algorithms, 112–113 Imaging coincidence, 135–165 dual-time point, 303 dynamic receptor, 394–397 receptor, 206 with SPECT, 135–137 Immobilization techniques, 128–129 IMRT. See Intensity modulated radiotherapy IND. See Investigational new drug Infantile spasms, 377–378. See also West syndrome Infection, 448–457 clinical applications of FDGPET and, 448–456 AIDS, 448, 450–451 CGD, 454–456

IBD, 452–454 osteomyelitis, 449–450 thyroiditis, 454 vasculitis, 451–452 differentiation of infectious/ inflammatory processes from malignancy and, 456–457 Inflammation, 448–457 clinical applications of FDGPET and, 448–456 AIDS, 450–451 CGD, 454–456 IBD, 452–454 osteomyelitis, 449–450 thyroiditis, 454 vasculitis, 451–452 differentiation of infectious/ inflammatory processes from malignancy and, 456–457 Inflammatory bowel disease (IBD), 452–454, 461–468 PET and cancers in patients with, 465–467 PET imaging compared to nuclear imaging techniques for, 462–465 physiologic FDG colonic activity of, 461–462 symptoms of, 452–453 Injection techniques, 7–10 with fingers and wrist, 9 with foot, 9 pediatric, key points, 8 INSS. See International Neuroblastoma Staging System Institute of Medicine (IOM), 59 Institutional review board (IRB), 60, 72 issues related to informed consent and assent with, 83–85 justice and, 85–86 risk assessment flowchart, 81 role of, 79–86 Interictal FDG, 364–366 Internal dosimetry absorbed dose of, 38–43

Index dosage of, 37–46 information on, 44 International Neuroblastoma Staging System (INSS), 243 Intracranial metastases, 201 Intraoperative mapping, 374 Intravascular thrombosis, 558 Intravenous (IV) placements, 4 Investigational new drug (IND), 48, 68–69 IOM. See Institute of Medicine IRB. See Institutional review board Iterative reconstruction algorithm, 162–164, 553 list-mode reconstruction, 164–165 MLEM algorithm, 162–164 K Kawasaki disease, 419–421, 451 Kennedy-Krieger Institute (KKI), 86 L Labeled amino acid PET studies, 326–327 Langerhans cell histiocytosis, 280 Laryngeal muscles, 527 LC. See Lumped constant L-dihydroxyphenylalanine (L-DOPA), 473 L-DOPA. See Ldihydroxyphenylalanine Learning disabilities (LDs), 341 LEHR. See Low-energy highresolution Lennox-Gastaut syndrome, 378 Lesch-Nyhan disease, 391 Leukemia, 509–510 Lewy bodies, 391 Ligand, 385 concentration of, 387 dopaminergic, 387 nonspecifically bound, 386 serotonergic, 387 tracer dose of, 386 Line of response (LOR), 105 Linear no-threshold (LNT), 61–62

LLD. See Low-level discriminator LNT. See Linear no-threshold Low-dose radiation, 84 Low-energy high-resolution (LEHR), 138 Low-level discriminator (LLD), 98 Low-level radiation biological effects of, 30–33 general views of, 62–63 overestimation of dangers of, 33 studies on, 31–32 LPSs. See Lutetium pyrosilicates LV. See Left ventricle Lymphadenopathy, 236, 452 Lymphoid tissue, 462 Lymphoma, 178, 220–239, 509–510 F-FDG-PET in, 222 initial staging of, 229–234 extranodal staging, 230–234 nodal staging, 229–230 lymphoblastic, 232 monitoring the response to therapy with, 234–239 follow up, with asymptomatic patients, 139 predicting response, 237–239 non-Hodgkin’s, 221–222 psychological variants in uptake of F-FDG, 222–229 BAT and skeletal muscle uptake of, 223–226 diffuse bone marrow uptake of, 226–229 thymus uptake of, 222–223 tonsillar, 551 Lymphomatous, 231, 534 M Magnetic resonance (MR), 177 multimodal imaging and, 485–497 Magnetic resonance imaging (MRI), 56, 485–497

571

brain tumors diagnosed by, 175 combination of, with PET, 489–497 false-positive/false-negative findings in, 493 functional, 73, 336 primary lesions and, 303 Magnetic resonance spectroscopy (MRS), 73, 509 Magnetoencephalography (MEG), 73 MAI. See Mycobacterium avium intracellulare Malignant fibrous histiocytomas (MFHs), 302 Mature teratoma, 202, 261 Maximum intensity projection (MIP), 530 Maximum likelihood expectation maximization (ML-EM), 113, 162–164 MBF. See Myocardial blood flow MC. See Monte Carlo algorithms M-CSF. See Monocyte/ macrophage-CSF Medical internal radiation dose (MIRD), 327 Medulloblastoma, 194 MEG. See Magnetoencephalography Membrane biosynthesis agents, 205 Meningioma, 178 Mental retardation, 346 Mesial temporal lobe regions, 362 Meta-Iodobenzylguanidine (mIBG), 244 images of, 245 Methionine, 182–183, 191–192 biopsy guidance, 192 carbon-11-labeled, 295–296 decrease in uptake in, 194 mean tumor-to-normal brain, 198 Methylphenidate, 391 MFHs. See Malignant fibrous histiocytomas

572

Index

mIBG. See MetaIodobenzylguanidine Michaelis-Menton equation, 386 Micrometastatic disease, 271 Minimal risk definition of, 63, 80 minor increase over, 80 MIP. See Maximum intensity projection MIRD. See Medical internal radiation dose Mixed lutetium silicates (MLSs), 102 ML-EM. See Maximum likelihood expectation maximization MLSs. See Mixed lutetium silicates Monocyte/macrophage-CSF (M-CSF), 228 Monte Carlo (MC) algorithms, 109 Mood disorders, 349–350 MR. See Magnetic resonance MR angiography (MRA), 486 MRI. See Magnetic resonance imaging MRS. See Magnetic resonance spectroscopy Mucocutaneous lymph node syndrome, 419 Multimodal imaging, 485–497 algorithms and accuracy of combined image analysis and image registration, 487 analysis and presentation of, 487–497 combination of MRI and PET, 489–497 necessary components for, 486 using PET and MRI, 485–497 indications for MRI in children, 485–486 Multislice rebinning, 154, 156 Musculoskeletal sarcoma, 267 Mustard operation, 422 Mycobacterium avium intracellulare (MAI), 428

Myocardial blood flow (MBF), 407 evaluation of, 408–410 quantification of, 410 Myocardial perfusion defects, 413 N N-acetylaspartate (NAA), 329 National Wilms’ Tumor Study Group (NWTSG), 257 NECR. See Noise equivalent count-rate Nephroblastomatosis, 262 Nephrogenic rest, 262–263 NET. See Norepinephrine transporter Neuroblastoma, 243–253, 510 FDG and, 246–248 mIBG, 244–246 other catecholamine/ catecholamine-like tracers and, 249–253 prognosis of, 243 Neurochemical PET imaging, 379–380 Neurodevelopmental disorders, 334–350 ADHD, 334–340 anxiety, 349–350 autism, 346–349 dyslexia, 343–346 mood disorders, 349–350 Tourette syndrome, 341–343 Neuroendocrine tumor, 314–315 Neurofibroma, 296 Neurofibromatosis type 1 (NF1), 313–314 Neurology, 503–506 of cerebral inflammatory diseases, 505 epilepsy and, 504–505 normal brain development and, 503–504 other neurological applications of, 505–506 Neuropsychiatric disorders, 334–350 ADHD, 334–340 anxiety, 349–350 autism, 346–349 dyslexia, 343–346

mood disorders, 349–350 Tourette syndrome, 341–343 Neuroreceptor-radioligand interaction, 385 Neurotransmitter imaging, 385–397 basic concepts of, 385–387 dopaminergic system and, 387–392 DAT, 389–392 dynamic receptor imaging and, 394–397 other systems, 392–394 acetylcholine, 394 norepinephrine, 393–394 opiate receptors, 393 serotonergic system of, 392 NF1. See Neurofibromatosis type 1 NHL. See Non-Hodgkin’s lymphoma NM. See Nuclear medicine N-methyl-D-aspartate (NMDA), 331 Nodal staging, 229–230 Non-attenuation-corrected images, 544 Non-Hodgkin’s lymphoma (NHL), 221–222, 491 Norepinephrine, 245, 393–394 Norepinephrine transporter (NET), 393–394 Normal brain development, 503–504 Normal mild asymmetry, 362 Nuclear imaging technologist children and, 5–6 communication and stages of development of, 4–6 flexible scheduling with, 6 imaging environment of, 10–13 injection techniques of, 7–10 as pediatric patient, 3–19 protocol with children of, 5 role of, 3 sedation and, 18 NWTSG. See National Wilms’ Tumor Study Group O Obsessive-compulsive disorder (OCD), 341, 350

Index OCD. See Obsessivecompulsive disorder Octreoscan, 314 Office for Human Research Protection (OHRP), 83 OHRP. See Office for Human Research Protection Oligodendroglioma, 180 Opiate receptors, 393 Ordered subset expectation maximization (OSEM), 113 Orlov’s condition, 161 Orlov’s sphere, 158 Orthopedic components, 273 OS. See Osteogenic sarcoma OSEM. See Ordered subset expectation maximization Osteogenic sarcoma (OS), 267, 278, 29,1540 Osteomyelitis, 449–450 P PACS. See Pancreatic arterial calcium stimulation Paget’s disease, 268 Pancreatectomy, 481 Pancreatic arterial calcium stimulation (PACS), 473 Pancreatic venous catheterization (PVC), 473 Paracentesis, 440 Paracentral gyri area, 328 Paraganglioma, 193 Parieto-occipital cavernous venous angioma, 370 Parkinson’s disease, 389, 390 Patient positioning, 130–131 Patient preparation, 125–126, 502–503 Patlak analysis, 326 Pediatric dose estimate, 43 Pediatric fever of unknown origin, 428–429 Pediatric injection techniques, 8, 11 Pediatric patient, 3–19.52–53. See also children bladder activities of, 12–13 fasting and glucose levels of, 14–15 flexible scheduling with, 6

fluorodeoxyglucose administration of, 15 fluorodeoxyglucose uptake phase and, 16 imaging environment of, 10–13 injection techniques for, 7–10 preparation of, 13–14 research regulations of, 47–57 Pediatric Research Equity Act (PREA), 59 Pentobarbital sodium, 28 Perilaryngeal tissues, 529 Peritonitis, 440 PET. See Positron emission tomography PET imaging of angiogenesis, 207 of apotosis, 208 for assessment of gene therapy protocols, 207–208 for autism, 346–349 common artifacts on, 543–562 artifacts related to image acquisition and reconstruction, 552–554 common causes of falsenegative findings, 561 common causes of falsepositive findings, 559–560 common causes of photopenic defects, 561 FDG distribution in, 546–552 iatrogenic artifacts, 554–558 compared to nuclear imaging techniques, 462–465 PET/SPECT imaging, 336–343, 345–349 Phenytoin, 379 Pheochromocytoma, 251, 252, 314, 512 Photopenic defects, 546, 557, 561 Physiologic FDG colonic activity, 461–462 PNET. See Primitive neuroectodermal tumor Pneumocystis carinii, 450 Pneumonitis, 556 Positron emitters, 95

573

Post-traumatic stress disorder (PTSD), 350 Prader-Willi syndrome (PWS), 505 PREA. See Pediatric Research Equity Act Prefrontal cortex, 350 Pre-scanning considerations, 121–128 interaction with patient and family for, 121–122 scheduling and logistics, 122–125, 125–126 coordination of related services, 122–124 diagnostic CT imaging with, 124–125 uptake phase, 126–128 Presurgical workup, 361–363 Presynaptic neuron, 249 Primary bone tumors, 267–297 assessment of response to treatment with, 286–289 changes in response to treatment in patients with, 288 histopathology of, 269–270 initial imaging of, 278–283 biopsy and sampling error, 281–282 false positives, 282–283 indication of prognosis, 280–281 local extent of, 281 tumor grading, 278–280 local tumor recurrence of, 289–290 metastatic disease and, 283–286 other PET radiopharmaceutical agents and, 291–296 C-Met, 295–296 F-« methaltyrosine, 293 FLT, 293–295 fluorine-18 fluoride, 291–293 prognosis of, 274–276 technical issues with, 296–297 treatment of, 271–274 Primitive neuroectodermal tumor (PNET), 178, 270

574

Index

R Radiation, 327. See also Dose; Low-level radiation background, 31 beneficial effects of, 32 biological effects of lowlevel, 30–33 characterizing risks of, 63–64 children’s sensitivity to, 30 legal interpretation of, 33 LNT model and, 61 risks of exposure to, 61–63 Radiation absorbed dose, 37–38 Radiation necrosis, 196–198 Radiation safety committee (RSC), 78 Radiation-induced pneumonitis, 556 Radioactive Drug Research Committee (RDRC), 47–48, 78 Radioactive tracers, 61–64 Radiopharmaceuticals, 291–296, 408 dosage of, 37–46 investigational use of, 67–69 local RDRC review and approval of, 67–68 research of, under IND application, 68–69 Radiotherapy intensity modulated, 199 standard external beam, 198 RAMLA. See Row action maximum likelihood algorithm rCBF. See Regional cerebral blood flow rCMR. See Regional cerebral metabolic rate RDRC. See Radioactive Drug Research Committee Rebinning data, 154–156 fourier, 112, 146, 156 multislice, 154, 156 single-slice, 112, 146, 154–156 Receptor antagonist raclopride, 388 Regional cerebral blood flow (rCBF), 324 Regional cerebral metabolic rate (rCMR), 349

Regional glucose hypometabolism, 364 Resuscitation carts, 23 Retinoblastoma, 316 Retransplantation, 422 Retroperitoneal brown fat, 532 Rhabdomyomatous differentiation, 263 Rhabdomyosarcoma, 512, 533, 539 Risk, 60–64, 81 classification, 79–83 minimal, 63, 80 Robertson v. McGee, 86 Row action maximum likelihood algorithm (RAMLA), 113 RSC. See Radiation safety committee S Sarcoidosis, 280, 507 Sarcoma, 540. See also Ewing sarcoma; Soft tissue sarcoma clear cell, 257 osteogenic, 267, 278, 291 rhabdomyo, 533 soft tissue, 302–308 SBV. See Standard beam volume Scanning bladder considerations for, 131 immobilization of the patient for, 128–129 of a patient, 128–132 patient positioning for, 130–131 sedation and general anesthesia for, 129–130 sequence for, 131 technologists’ roles for, 131–132 timing of, 128 Scans. See FDG-PET scan; Magnetic resonance imaging; Positron emission tomography Schizophrenia, 388, 505 Sclerosing cholangitis, 467 Sclerosis, 374 Sedation, 18, 66 alternatives to, 19

approach to, 26–28 for children 1 year or older, 27 for children 3 months or younger, 27 circumstances of, requiring assistance of anesthesiologist, 24 common issues of, in children, 21–28 guidelines of, 21–23 monitoring equipment for, 23 nuclear imaging technologist and, 18 pediatric patient and, 18 resuscitation carts for, 23 risk factors of, 22 tips for successful, 26–27 Serotonergic ligand, 387 Serotonergic system, 392 Serotonin, 348 Short-time inversion recovery (STIR), 272, 495 Single photon emission computed tomography (SPECT), 11, 73, 92 ADHD imaging by, 336–338 ADHD in children and, 336–340 ADHD medications by, 338–340 autism and, 346–349 changes in cerebral blood flow, 324 correlation of, to other modalites, 327–329 dyslexia imaging by, 345–346 ictal, 364–366 imaging with, 135–137 TS imaging by, 341–343 SLE. See Systemic lupus erythematosus Society of Nuclear Medicine Technologist Section (SNMTS), 132 Society of Pediatric Oncology (SIOP), 257 Soft tissue sarcoma, 302–308 PET’s role in, 302–307 evaluation of primary lesion, 302–304 prognostic information, 307

Index staging for metastases, 304 therapy/detection of recurrence, 304–307 treatment evolution of, 305 SPECT. See SIngle photon emission computed tomography Splenic uptake, 532–533 SPM. See Statistical parametric mapping Spontaneous DNA damage, 77 SSS. See Single scatter simulation Standard external beam radiotherapy, 198 Standard uptake values (SUVs), 110, 178 Statistical parametric mapping (SPM), 505 Status postradiation, 176 Stereotactic biopsy, 183, 197 Stereotactic radiosurgery, 198 STIR. See Short time inversion recovery Streptococci, 449 Striatal dopamine, 388 Subdural electrodes, 496 Supraclavicular brown fat, 531 Surface glucose transporter proteins (GLUT), 432 SUVs. See Standard uptake values Systemic lupus erythematosus (SLE), 429 T Takayasu arteritis (TA), 452 Temporal lobe epilepsy (TLE), 366–369, 392 Terminal deoxynucleotide endlabeling (TUNEL), 208 TGA. See Transposition of the great arteries

Thalami, 379, 528 Thermogenesis, 530 THPVS. See Transhepatic portal venous insulin sampling Three Mile Island accident, 33 Thymidine, 45 Thymus uptake, 222–223 benign, 223 characteristic inverted vshaped uptake in, 547 Thyroiditis, 454 Time-of-Flight Scanners, 113–114 TLE. See Temporal lobe epilepsy Tonsillar cancer, 435 Tonsillar lymphoma, 551 Total parenteral nutrition (TPN), 15 Tourette syndrome (TS), 341–343, 391 background of, 341 PET/SPECT imaging in, 341–343 TPN. See Total parenteral nutrition Tracer injection, 205 Transhepatic portal venous insulin sampling (THPVS), 482 Transposition of the great arteries (TGA), 416–417 Traumatic brain injury, 505 TS. See Tourette syndrome Tuberous sclerosis, 374 TUNEL. See Terminal deoxynucleotide endlabeling Tyrosine (Tyr), 195 U Ultrasonography (US), 262, 431

575

UPMC. See University of Pittsburgh Medical Center Uptake phase, 126–128 US. See Ultrasonography V Vasculitis, 421, 433, 451–452 Ventral prefrontal cortex, 336 Vocal chords, 547 W Waldeyer ring, 529 WBC. See White blood cell Wernicke’s area, 345 West syndrome, 377–378 White blood cell (WBC), 462 WHO. See World Health Organization Whole-body imaging, 17 Wilms’ tumor, 256–264, 510 accurate staging of, 259 bilateral, 260–262 differentiation of residual tumor from other entities and, 263–264 epidemiology of, 256 neophrogenic rest and, 262–263 pathology of, 256–257 potential applications of PET/PET-CT imaging to, 258–264 bilateral, 260–262 staging, 258–260 prognostic factors of, 257 treatment of, 257 Wilson’s disease, 391 World Health Organization (WHO), 185, 221 Y Yolk sack tumor, 488